CA2238762A1 - 2-thioxo-imidazolidin-4-one derivatives and their use for increasing hdl cholesterol concentration - Google Patents

Abstract

Compounds and a method for increasing the HDL cholesterol concentration in the blood of a mammal in need of increased HDL cholesterol blood concentration, which comprises administering to said mammal, orally or parenterally, a compound of formula (I) wherein R is alkyl; a substituted or unsubstituted aromatic N, O or S heterocycle; substituted or unsubstituted aryl, arylalkyl, benzhydryl or indanyl, in which the substituents are one to three members independently selected from the group consisting of alkyl, alkoxy, alkylthio, alkenyl, alkynyl, halo, perfluoroalkyl, perfluoroalkoxy or hydroxy; and R1 is aryl, alkyl, alkenyl, alkynyl or substituted aryl where the substituents are one to three members independently selected from the group consisting of alkyl, alkoxy, alkylthio, alkenyl, alkynyl, halo, perfluoroalkyl, perfluoroalkoxy or hydroxy.

Description

CHOLESTEROL CONCENTRATION.
The present invention relates to co.~lyuu~ds for increasing HDL cholesterol col-~f..,l.~linn in the blood of a ..-~ , to their use in this method of ~ l, to S phh.,..~r~llir~l compositions col-l~ the compounds and to a process for a~on of the cc,lll~u.lds.
Numerous studies have ~le~o~ d that both the risk of CUl~Jn~U,y heart disease (CHD) in hl~m~n~ and the severity of çxl.~ .;".~"I,.l atherosclerosis in animals are inversely correlated with serum HDL chnlest~rol (HDL-C) c(~,~re.,l, ~ n~ (Russ et al, Am. J, Med.. 11 (1951) 480-493; Gofman et al, Ci~c~ hon~ 34 (1966) 679-697;
l~llerand Miller, Lancet, 1 (1975) 16-19; Gordon et al, Circul~tiQn~ 79 (1989) 8-15, Sla..l~rel et al, N. En~l J. Med.. 325 (1991) 373-381; R~1imon et al, T ~h. Invest.. ~Q
(1989) 455-461). Atherosclerosis is the process of ~r~llmlll~hon of cholesterol within the arterial wall which results in the occlusion, or stenosis, of coronary and cerebral 15 arterial vessels and subsequent myocardial infarction and stroke. Angiographical studies have shown that elevated levels of some HDL particles appears to be correlated with a decrease in the number of sites of stenosis in the co~vl~y arteries of hllm~n.c (Milleretal, Br. Med. J.. 282 (1981) 1741-1744).
There are several ..~h~ m~ by which HDL may protect against the 20 progression of atherosclerosis. Studies in vitro have shown that HDL is capable of removing cholesterol from cells (Picardo et al, Arteriosclerosis, 6 (1986) 434-441).
Data of this nature suggests that one ~nh~th~rogenic yl~.ly of HDL may lie in its ability to deplete tissues of excess free cholesterol and eventually lead to the delivery of this cholesterol to the liver (t'Tlom~et, J. Lipid Res.. ~ (1968) 155-167). This has been 25 supported by expcl;-l-el-t~ showing effl ri~ntLIall~rt;l of cholesterol from HDL to the liver ~Glass et al, Circ~ tiQn~ 66 (Suppl. I~ (1982) 102; MacKinnon et al, ~. Biol.
~hem., 261 (1986) 2548-2552). In ~ ition~ HDL may serve as a reservoir in the circulation for a~ol~-~teills n.oces~ry for the rapid metabolism of triglyceride-rich t;hls (Grow and Fried, J. Biol. Chem.. 25~ (1978) 1834-1841; Lagocki and Scanu, J. Biol. Chem.. 255 (1980) 3701-3706; Schaefer et al, J. Lipid Res.. 23 (1982) 1259-1273). Accordingly, agents which increase HDL cholesterol concentrations are useful as anti-atherosclerotic agents, particularly in the Ll~a~ ,n~ of dysli~ t;il-emias and coronary heart disease.
US 5,137,904 discloses a group of thiohydantoin derivatives of the formula 9~ NH
~Y_X

in which Z is alkyl, ~h.,nylalkyl, phenyl or ~-lb~ A phenyl, where the ~ul)~LiL~.,nt is a halogen, alkyl, alkoxy or halogenated alkyl group; X is phenyl, halophenyl, aLkyl, alkenyl, or alkynyl; and Y is S or O. These compounds inhibit collagen-im1lleed and S ADP-in~ e~l platelet ag~,g,~l;on EP 0584694 andWO 93/18057 disclose a group of imirl~7~lidin-3-yl henzoyl or aLkanoyl amino acid derivatives as inhibitors of cell-cell adhesion for use in inhihition of Lh~ bocyte aggregation, met~et~ei~ and osto.ocl~et formation. Chronic ~rl,l.,n;~ Lion for ~ ion of arteriosclerosis and Lhloll,hosis is ~lieclose~l.

H20C~ I2)n~ N' ' N~ N- R2 R O~Rl in which Y = -(CH2)n-CO- or -Ph-CO- .
JP 04,297,461 discloses a group of 2-thiohydantoin coln~oullds of the following formula, said to be useful as anti-bacterial, anti-viral, anti-il.ll~.. ~tc-ry and anti~ ....l.nlir. agents:

'NJ~N-R2 Os~ R3 20 where Rl is lower alkyl, lower alkenyl, phenyl~lower)alkyl or substituted phenyl with 1-3 groups chosen from lower alkyl, lower alkoxy, halogen, lower alko~yc~l.vnyl or hydroxy;
R2 is either hydrogen or alkanoyl; and W O 97/19932 PCT~US96/19164 R3 is hydrogen, lower aLkyl, phenyl, phenyl ~lower) aLkyl, or a lower alkylthio,lower alkyl group that can be snb~ .l. A with one to three phenyl groups that have had a lower alkoxy group.
EP 0578516 discloses a group of 2-thiohy~ntc in~, said to be useful anti-S androgenic agents for L~ t of vaTious cancer, of the formula:

where X is oxygen or sulfur, Y is oxygen, sulfur or NH
R1 and R2 are cyano, nitro, halogen, trifluc, ~ yl, or a free or çst~ri~çd c~bo~ylic acid or salt;
R3 is hydrogen, alkyl, aL~cenyl, allcynyl, aryl or aryl-alkyl;
R4 and R5 are hydrogen, optionally ~ul)~ ut~ d alkyl, or cycloalkyl.
US 5,411,981 fli~closes compounds closely related to EP 0578516, supra, where R4 and R5 are both methyl.
US 3,923,994 discloses a group of 3-aryl-2-thiohydantoin derivatives of the following formula, which have anti-arthritic activity:

R1~
~

where Rl and R2 are hydrogen, chloro, bromo, fluoro or aL~yl of 1-2 carbon atoms.
' JP 73 87,030 discloses a group of 3-phenyl-2-thiohydantoin derivatives useful as herbicides.
~ 25 US 4,473,393 discloses agroupof pesticid~l thiohydan~ compositions.
In accordance with this invention there is provided a compound of formula I:

R'N~Rl I

w}.~
R is alkyl of 1 to 6 carbon atoms; a s~ ,t~ ~ or unsub~ u~cd aromatic N, O
or S het~,.~;yde having 4 to 6 carbon and one hetero ring ...~ , substituted or S unsubstituted aryl of 6 to lQ carbon atoms, arylalkyl of 7 to 12 carbon atoms,benzhydryl or indanyl , in which the substit-~.nt~ are one to three . . .~
in~le~.~-lf..~ly s~lectç~ from the group consisting of aLkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon ations, alkylthio of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, halo, perfluoroalkyl of 1 to 6 carbon 10 atoms, perfluoroalkoxy of 1 to 6 carbon atoms or hydroxy; and Rl is aryl of 6 to 10 carbon atoms, aLkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms or ~u~LiluLcd aryl of 6 to 10 carbon atoms where the substit. l~.nf~ are one to three ".~,~ in~lçp~nfl.ontly s~lect~A from the group con~i~ting of alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon ations, alkylthio of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, halo, ~lnuol~alkyl of 1 to 6 carbon atoms, perfluoroalkoxy of 1 to 6 carbon atoms or hy~y, for use in the tre~tm~nt of m~mm~
A ~l.,r~,..Gd embodiment of the invention provides a compound of formula I in which R is substit lt~q~l phenyl where the substitllentc are two mc;lllb~ of the group 20 co~ ;g of alkyl of 1 to 6 carbon atoms, perfluoroalkoxy of 1 to 6 carbon atoms, halo, or ortho sllb~ lclhylenc or l~ lene and Rl is aLkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms.
Another preferred embodiment of the invention provides a cc,ml~ound of formula I in which R is substituted phenyl where the ~ub~ uents are a halo and an alkyl group of 1 to 3 carbon atoms or ortho substit-lte.(l L~ e~,ylene and Rl is aLkyl of 1 to 3 carbon atoms, alkenyl of 2 to 4 carbon atoms or alkynyl of 2 to 4 carbon atoms.
Another preferred embodiment of ~e invention provides a coll,l)ound of formula I in which R is substituted phenyl where the substitue.nt~ are chloro or fluoro in the 4- or 5- position and an alkyl group of 1 to 3 carbon atoms and Rl is alkyl of 1 to 3 carbon atoms, alkenyl of 2 to 4 carbon atoms or alkynyl of 2 to 4 carbon atoms.

W O 97/19932 PCTrUS96/19164 Certain of the ccml~uullds of the present invention are novel and comr~e a further aspect of the present invention. Thus, accol~ing to a further aspect of the present invention there is provided a coln~>ul.d of formula I as described abovewherein Rl is alkyl of 1 to 6 carbon atoms and R is alkyl of 1 to 6 carbon atoms, naphthyl, benzhydryl, fluo~nyll~L'Ilyl, l~h~ L~yl, l-~fluorophenyl)ethyl, S-chloro-2-methc~y~h~ yl, llinuol~)n~Glllo~ylJhenyl, triflu~ ,Lllyll,henyl, methylsulfanyl-phenyl, pyridyl or the group of formula II

R3--~

where R2, R3 and R4 together are 2-chloro, 4-fluoro, 2,4-chloro or 2,6- chloro, or R2 is hydrogen, R3 is a halogen in 3-position and R4 is alkyl of 1 to 6 carbon atoms in 4-position, or R2 is alkyl of 1 to 6 carbon atoms and R3 and R4 are, independently, hydl~gell or aL~cyl of 1 to 6 carbon atoms or R3 is a halogen and R4 is hydrogen;
or Rl is alkenyl of 2 to 6 carbon atoms, R is is the group of formula II
where R2 is aLkyl of 1 to 6 car'oon atoms and R3 and R4 are, independently, hydrogen or aLtcyl of 1 to 6 carbon atoms, or R2 is hydrogen and R3 and R4 taken together are ortho substituted llh~l~,L'Ilylene or LeLI~lleL'llylene, or R2 is alkyl of 1 to 6 carbon atoms, R3 is halogen and R4 is hydrogen, or R2 is hydrogen, R3 is halogen in 3-position and R4 is alkyl of 1 to 6 carbon atoms in 4-position;
or when Rl is alkynyl of 2 to 6 carbon atoms, R is a group of formula II
where any two of R2, R3 and R4 are, in-l~per~ ntly, alkyl of 1 to 6 carbon atoms, halo, perfluoralkyl of 1 to 6 carbon atoms, perfluoralkoxy of 1 to 6 car'oon atoms, or, taken together, are ortho substituted llilnGLllylene or L~Ll~nell~ylene;
or when Rl is aryl of 6 to 10 carbon atoms or arylalkyl of 7 to 12 carbon atoms, R is the group of formula II

W O 97/19932 PCT~US96/19164 where R2 is aL~cyl of 1 to 6 carbon atoms, R3 is a halogen and R4 is hydrogen, or R2 is hydrogen, R3 is a h~logçn in 3-position and R4 is alkyl of 1 to 6 carbon atoms in 4-position.
When any of R, Rl~ R2, R3 or R4 is aLIcyl it is preferably aL~cyl of 1 to 3 carbon atoms, espeçi~ly methyl or ethyl, or any two of R2, R3 and R4 when taken oge~ rareortho.,~ ut~lllim.Lllyl~ncorl~n..l ll.ylene.
When Rl is aL~enyl of 2 to 6 carbon atoms it is preferably allyl, When R2 or R3 are halogen they are preferably intlppen~l~ontly~ ~hlcrine or fluorinP, especially in the 2-, 4-, and/or -6 position~ When R2 or R3 are perfluoralkyl of 1 to 6 carbon atoms, perfluoraL~oxy of 1 to 6 carbon atoms When Rl is alkynyl of 2 to 6 carbon atoms it is preferably ethynyl, ~yl or butynyl, especially prop-2-ynl.
When R is aryl of 6 to 10 carbon atoms it is preferably, phenyl or naphthyl, thelatter being preferably, 2-naphthyl. When R is araL~cyl of 7 to 12 carbon atoms, it is preferably benzyl or ~ e..-,l1.yl.
When R is fluorophe~ ,LI-yl, it is preferably 4-fluorophenyllllelllyl.
When R is l-(Ilu~ ph~.lyl)ethyl, it is preferably 1-(4-Iluu~ .he.lyl)ethyl.
When R is trifluoromethoxyphenyl, it is preferably 4-1linuol~-methoxyphenyl.
When R is methylsulfanylphenyl, it is preferably 2-methylsulfanylphenyl.
When R is pyridyl, it is preferably 3-pyridyl.
The most ~.ef~l~d ccJIll~ou"ds of this invention based upon their potency and overall activity prcfile in the standard e~ ~.l~ test model are:

3-(5-Chloro-2-methylphenyl)- 1 -methyl-2-thioxo-imicl~701idin~-one 3-(3-Chloro-2-me~ylphenyl)-1-methyl-2-thioxo-;.~ .. lidin-4-one 3-(4-Chloro-2-meth~ hc.lyl)-l-methyl-2-thioxo-imi-1~7~.1idin-4-one 3-(Indan-5-yl)-l-methyl-2-thioxo-imi~7olidin-4-one 3-(2,6-Diiso~rul)ylphenyl)-l-methyl-2-thioxo-imi-l~7clidin-4-one 3-(2-Ethyl-6-is~ ylphenyl)- l-methyl-2-thioxo-imi(l~701idin-~one 3-(2-Ethyl-6-me~ylphenyl)-l-methyl-2-thioxo-imirl~7~1idin-4-one 3-(5-Chloro-2-methylphenyl)- 1 -ethyl-2-thioxo-imid~ 7~1idin-4-one 3-(2,6-Dichlol~plle.~yl)-l-ethyl-2-thioxo-imi~l~7nlidin-~one l-E~yl-3-~4-fluo,~ hcllyl)--2-~ioxo-im~ 701itlin-4-one 1 -Ethyl-2-thioxo-3-(4-l,inuu.u~ ,Ll-v~y~henyl)-imi~Q7oli(1in-4-one 3-(2,6-DimethyllJh~url)-l-ethyl-2-thioxo-imi~7olidin-4-ûne 1-Ethyl-3-isobutyl-2-thioxo-imirl~7n~ n-4-one 3-(2-Chlu~ul>h~lrl)-l-ethyl-2-thioxo-~ Q7~liriin-4-one l-Ethyl-3-(2-tolyl)-2-thioxo-imi~Q7Olidin-4-one 3-(2-Chloro-6-1l,eLhylphll-yl)- l-ethyl-2-thioxo-imiAQ7olidin-4-one 1 -Ethyl-3-(5-fluoro-2---~Lllyll)h~l-yl)-2-thioxo-imi~lQ7olidin-4-one 3-(2,6-Diisopropyl~h~.lyl)- 1 -ethyl-2-thioxo-imi-1~7.oli-1in-4-one l-Ethyl-2-thioxo-3-(2-llillu~v~ ylphenyl)-;...i.lQ~.oli iin-4-one l-Ethyl-3-(2-ethyl-6-l~k~Ll-yl~he--yl)-2-thioxo-imirlQ7cli~1in-4-one 3-(2-Chloro-4-methylphenyl)- l-ethyl-2-thioxo-imiflQ7olidin-4-one 3-(2,4-Dichlol~phenyl)-l-ethyl-2-thioxo-imidQ7nlidin-4-on 3-(2,4-DillleLl~rl~h~n~l)- 1 -ethyl-2-thioxo-imif'iQ7.olidin-4-one 3-(2,5-Dimethyl~hG.~yl)-l-ethyl-2-thioxo-imi~lQ7.olidin-4-one l-Ethyl-2-thioxo-3-(2,4,5-~ ~lllrlph~llyl)-imi-lQ7t 1i-1in-4-one 1 -Ethyl-3-(2-isoprvpylphenyl)-2-thioxo-imi~Q7nli~1in-4-one 1-Ethyl-3-(2-eillyl~ lyl)-2-thioxo-imitlQ7c)li~lin-4-one 3-(S-Chloro-2-l,~ hylphenyl)-l-phenyl-2-thioxo-imi;Q7~ 1in-4-one 3-(5-Chloro-2-"lGLlilyl~henyl)-l-isop~vpyl-2-thioxo-imiriQ7nlidin-4-one 3-(2,6-Dimethylpheny~ -isopropyl-2-thiûxû-imi~Q7olidin-4-one 3-(2-Ethyl-6-~ hyl~henyl)-l-isu~ ~yl-2-thioxo-imiflsl7olidin-4-one l-Butyl-3-(4-nuo~u~ ellyl)-2-thioxo-imi~lQ7.oli-'iin-4-one 1-Allyl-3-(2~6-~ yl~henyl)-2-thioxo-imi~Q7~ in-4-one 3-(2,6-Dimethylphenyl)-l-(pr~p-2-ynyl)-2-thioxo-imid~Q7.olidin-4-one 3-(3-Chloro-4-lllt;ullyl~hellyl)-l-methyl-2-thioxo-imi~lQ~7.olidin-4-one 3-(2-Elhylpll~llyl)- 1 -methyl-2-thioxo-imir~Q7nlidin-4-one 1 -Methyl-3-(2-is~lu~ylyhenyl)-2-thioxo-imi~lQ7olidin-4-one 3-(4t-Butylphenyl)-l-methyl-2-thioxo-imi~lQ7.oli(1in-~ûne l -Allyl-3-(5-chloro-2-l~ei'ilyll~henyl~-2-thioxo-imi~i~7.oli~iin4-one 3-(5-Chloro-2-l~ lylph~llyl)-l-(prop-2-ynyl)-2-thiûxo-imi~Q7oli~in4-one l -Ethyl-3-(2-ethyl-6-isoprûpylphenyl)-2-thioxo-imi~lQ7olidin-4one.
A ~,~fc.,~d use of the compounds of formula I or method of treQtment using the c~lu~ou"ds is for incnasing ~)L cholesterol col~ç~ n';on in the blood of a ~ .llAl, by Qnmini~t~ingto said l.~"..~Ql an amount of a substituted 2-thioxo-imifiQ7.olinin 4-one as herein defined, sufficient to L~clcase that HDL rh~le: ~,1 concc~ tion, and this ,~,~lcse,lls further asyects of the present invention.
The colllpoul~ds of the invention can be yl~cd readily according to the following reaction scheme or l-.o3;r;~ ;oll thereof using readily available starting m~to.ri~ , reagents and convçnl;onAl synthetic ylOcGdu~,s. It is also possible to m~ke use of variants of these process steps, which in Ille~lls~ es are known to and well within the ~lClJ~Lldk~l,y skill of the medicinal chemi~t In the following reaction sc~h~m~-, R2 is hydrogen or alkyl of 1 to 6 carbon atoms and X is a halogen.

H~<CO2R2 Rl-NH2 EH~<CO2R2 + Rl-NH2.HX
X 'NH-RI
(2a) (2b) R--NCS
H R~ 1 Base R--NCS " R~ N~, N ~C02R2 \~e Base (3a) ~f EtOH/ S
C~ ' (3b) ,N~N~
S
N-sllh~ ~1 amino acids (2a) were ~lct)ar~d by reacting the corresponding oc-halo acids (1) with the ~ riate amines (excess). The reaction was carried out either neat or in water at Al~h e~ for 18 hours. One equivalent of the amine 15 scavenges the hydrohalide formed during the alkylation forrning the amine hydrohalide (2b) as a side product. The N-alkyl amino acids (2a) were either puri~led by cryst~llt7~tion from an ~ iate solvent, orreacted with the isothiocyanates as crude product Ini~ cs colll~;..;..g ~e amine hydrohalide salt. R.~c~ion of 2a with isothlo iy~ales is ca~ied out in chlolvÇ~ or methylene chloride in the presence of a W O 97119932 PCT~US96/19164 base such as triethyl amine. The ~ lu~ is heated at reflux for 3 to 18 hours. The reaction affords either the Ll~iuu~a (3a) or the thiohyd~in (4) directly (clepen-ling on dle nature of Rl). Cyr1i7~tinn of 3a to the thiohyda,ltûL~ (4) is accomplished by l~llwul g in ethanol for 2 to 3 hours in the presence of base (triethyl amine). In the case 5 of reacting the crude yl~xlu~il llfi~LulG (2a & 2b) with i~othiocyanates, the thiourea (3b) is formed as a side y~lucl along with 4. Pu~ of 4 was achieved by 1) fr~cti~
crysts-11i7~ti-~n, 2) flash cl-l.,...~lr~ rhy, 3) eYtr~rtinP 3b in 2N hydroch1nric acid or 4) ~ip;l~ g 3b as its hydrochloride salt from an ~ylu~liale solvent such as ethyl acetate or diethyl ether.
This invention also provides ph~rm~ce~1tir~1 cc,.ll~,o~ n~ comrri~e 3 of the 2-thioxo im;~l~7~ 1in-4-one derivatives either alone or in com1~ ;on with excipients (i.e. ph~rm~relltir~lly ~r~ept~'~ m~t~i~1~ with no ph~ Aro1Ogir~1 effects). Suchcomposition~ are useful in the ~ of ~ vsclerotic con.1;l;uns such as dysli~-o~ ~~ and COlull~y heart rli~ea~et in that they in.;l~,ase the blood serum 15 high density li~o~l~t~;-- con~entration of ",~-"-"~1~ treated with the com~ou.-ds.
The precise dosage to be employed depends upon several factors including the host, whellle~ in vet~lll~ e or human mr~lirinr the nature and severity of the condition being treated, the mode of ~lmini~t~ti--n and the particular active subst~nre employed. The colll~owlds may be ~ . ~1 by any convrnti()n~1 route, in 20 particular enterally, preferably orally in the form of tablets or capsules. ~1mini~trred culllyounds can be in the free form or ~ rG~ lly acceptable salt foqrn as ç~liate, for use as a yh~ relltir~l~ particularly for use in the prophylactic orcurative ~ of athe~scl~,lv~.is and seq11e1~~ (angina pectoris, myocardial inr~;~n, aTrhythmias, heart failure, kidney failure stroke, y. . ;yh. .,,1 arterial 25 occlusion, and related disease states). These n~ea~ s will slow the rate of progress of the disease state and assist the body in l~,~C ~ing t'ne process direction in a natural mel.
Any suitable carrier known to the art can be used to prepare the pharm~re11tira1colllyosilions. In such a coll-yo~ ion, the carrier may be a solid, liquid or mixture of a 30 so~id and a liquid. Solid compositions include powders, tablets and capsules. A solid carrier can be one or more substances which may also act as a ~1a~ulillg agent, lubricant, so1nhi1i7er, ~7u~y~lldillg agent, binder, or tablet ~ integrant. In powders, the carrier is a finely divided solid which is in a~ lu -, with the finely divided active ingredient. In tablets the active ingredient is mixed with a carTier having the neces~

binding properties in suitable plu~llions and co...l-~ch~1 in the shape and size desired.
S1~it~h1e solid caIriers are m~ - carbonate, m~ ;.. stearate, talc, sugar, 1R~tC.Se, pectin, dex~in, starch, gelatin, tr~ nth, methyl cellulose, hy~l~u~ylllethyl cellulose, sodium c~l~"yl~ yl cÇll~lQse~ a low melting wax, cocoa butter, and the S like. F.nr~ps~71~tin m~t~.ri~1~ may also be employed with the cc,lll~uullds of this invention, and the teqm "c~ ox;l;on" is int~n<l~l to include the active ingredient in co.-.h;~ with an e-~ p~u~ m~t~i~1 as a fo~ tion, with or willloul other carriers. Cachets may also be used in the delivery of the anti-atherosclerotic m~Ai~m~.nt of this invention.
Sterile liquid cr"~.~ ;ons include solutions, ~us~nsions, em~ ion~ syrups and elix*s. The cc"~l~ounds ûf this invention may be dissolved or suspended in the h,..~ G~ 11y ~ rt~l~ carrier, such as sterile water, sterile organic solvent or a of both. P~,r~ably the liquid carrier is one suitable for parental i.~jccl;o~.
Where the co~llpou,~ds are snffi~ ient1y soluble they can be dissolved direcdy in normal 15 saline with or without the use of suitable organic solvents, such as propylene glycol or polyethylene glycol. If desired, dispersions of the finely divided cc.lll~oullds can be made-up in aqueous starch or sodium carboxymethyl cel1111Ose sn1ution, or in a s-lit~
oil, such as arachis oil. Liquid ~h,.. ~l~e.utic~1 compositions which are sterile solutions or suspensions can be utilized by i~ r, LIlL~ iLoneal or ~u1~ h"K~
20 injection. In many ~ es a liquid co.~ osilion form may be used instead of the ~,fcll~d solid oral method of ~1, l l; .~ . aLion.
k is plGre.,.,d to prepare unit dosage forms of the colll~,oullds for standard ~lmini~tration regimt.n~. In this way, the col"~osiLion can be subdivided readily into smaller doses at the physicians direction. For example, unit dosages may be made up 25 in p~ teA powders, vials or ampoules and preferably in capsule or tablet form. The active ccnly~Ouild present in these unit dosage forms of the ~~ o~i~ion may be present in an amount of from about one gram to about fifteen grams or more, for single or mn1tir1e daily ~ ll alion~ according to the particular need of the patient. The daily dose of active cu-mpound will va~y flPpenl1ing upon the route of ~rlmini~tration, the 3Q size, age and sex of the patient, the severity of the disease state, and the response to the therapy as traced by blood analysis and the patients recovery rate. By initi~ting the ~l"~.l~l regimen with a minim~1 daily dose of about one gram, the blood levels of HDL and the l~alients sy,~ ;C relief analysis may be used to de~ e whether a larger dose is in-lir~t~ Based upon the data presented below, the projected d~ily dose W O 97/19932 PCT~US96/19164 for both human and ~et~ use will be from about 10 to about 200 milligr~ms/kilogram per day. However, in gen~.r~l, s~ti~f~tory results are i"~ ~ to he ol~ ed at daily dosages in the range of from 400 milligrams to about 200() rnilligrams, conv~ tly ~(lmini~tt~red in divided doses two to four times a day.
S The ability of the co~ vu~ds of this invention to ill.,~se blood serum HDL
levels was est~hli~h~ by the following ~ procedure for ~1~-h~ ;nn of HDL cholesterol:
Male Sprague-Dawley rats weighing 200-225 g are housed two per cage and fed Purina Rodent Chow Special Mix 5001-S ~u~len~ eA with 0.25 % cholic acid and 1.0 % cholesterol and water ad libitum for 8 days. Each test s.lb~ u~e is t~ .ed to a group of six rats fed the same diet with the test diet mixed in as 0.005 - 0.1 % of the total diet. Body weight and food con~ul~lion are l~Cu~ prior to diet ~mini~tration and at l~.,,,;.lAIio,~ Typical doses of the test subsl~lces are 5 - 100 mg~g/day.
At ~e~ n, blood is coll~ort~A from A.~f.;,l~ rats and the serum is sc~al dL~d by centrif~ tion Total serum chnlest~ol is assayed using the Sigma Di~..o~ s el,~l~la~ic kit for the d~t~ l;on of Ghol~stt~rol, Sigma Procedure No.352, motlifieA for use with ninety-six well microtiter plates. After ~ ill.l;on with water the reagent cont~ins 300 U/l chol~ ~,1 oxi~ e, 100 U/l cholesterol e~ asc,1000 Utl horse radish peroxidase, 0.3 mmole~ mino~ .yline and 30.0 mmnl~.s/l p-hy~yl~~ e~..lfonate in a pH 6.5 buffer. In the reaction cholesterol is oxidized to produce hydrogen peroxide which is used to form a qnin~ ,e dye. The col-r~ l;o~ of dye formed is mea~uled ~;lLu~ùlon~ llic~lly by absc,ll,ance at 490 nm after inr~ tif~n at 25C for 30 .~ l s The concenLIdLion of cholesterol was 25 ,1~ f~ for each serum sample relative to a co,n.~ ;ial standard from SigmaHDL cholesterol collce~ ns in serum are d~t~,lll~i,-ed by separation of li~u~uL~;n classes by fast protein liquid C~ AIO~ Y (E~PLC) by a mo~ n.~tion of the m~hod of Kieft et al., J. I~ipid Res.. ~ (1991) 859-866. 25 ul of serum is inje~d onto Superose 12 and Superose 6 (Pl.~macia), in series, with a column buffer of 0.05 MTris (2-amino-2-hy~ yl~lllyl-1,3-prop~neliol) and 0.15 M sodium chloride at a flow rate of 0.5 ml/min. The eluted sample is mixed on line with Bo~hring~r-~nnheim cholest.orol reagent pumped at 0.2 mUmin. The ccnnl,illed eluents are mixed and incuh~ted on line through a knitted coil (Applied Biosciences) .~ ~1 at a t~ ~la~ of 45C. The eluent is ~l-w~ cd by measuring absoll,ance at 490 nm and W O 97/19932 PCTrUS96/19164 gives a c~ ous al)sc,ll~ ce signal p~ul liollal to ~e cholçst~-rol C~n~el~ t;Q~ . The relative c~ ;on of each li~ h in class is c~lc~ e~l as the per cent of totalabso~ ,ce. HDL cholF~terol concentration, in serum, is c~ t~ as the per cent of total chnl~ost~l as ~ n~ by FPLC mllltipliçd by ~e total serum çh~
5 concentration.
Test cc,.ll~u~-ds were ~ t~ at a dose of 100 mg/kg. The duration of was eight days. The compounds of the present invention increase HDL
cholesterol conce.l~ tions as ~ l in Table I:

Tab e I
Compound of HDL C:holesterol Level Example I~.e.. ~-~ (%) l~i 132 W O 97/19932 PCT~US96/19164 Table I (Continued) Compound of HDL Cholesterol Level Example Ine~ %) 21 18û

CA 02238762 l998-05-27 Table I ~Continued) Compound ofHDL Cholesterol Level Example Increase (%~

The following examples are p,~,s~,lLed to illn~t~ the pr~{1ncticn of l~,~s~ Lh~e cc,lnl,uunds useful in dle method of this invention, rather than as a limit 5 to the scope of applicant's invention:

~.XAMPI,h'. 1 3~ hloro-?-metlvl~heny~ netbyl~-thio~o-~ 7olidin-4-one A Illh~Lulc of s~-;oshle ethyl ester hydrochloride (7.68 g), 5-chloro-2-methylphenyl-isothiocyanate (9.18 g), triethyl amine (12 g~ and chlc,l~ro.lll (200 mL) was heated at reflux for S hours. The mixture was cooled to ~n~l e ~l te ..~

washed with lN HCl (2x200 rnL3, then with water (200 miL) The organic phase was ~v~ ..t~l to dryness. The residue was crys~lli7~A from ethanol to give the titleeo,,lyc~u~d (9.2 g) as atan solid, m.p. 132-134 C. Anal. Calcd. forCll Hll Cl N2 ~
S: C, 51.87; H, 4.35; N,11.00. Found: C, 51.79; H, 4.12; N, 10.73. Mass ~ lu"
(EI, M.+) m/z 254/256.

F'X AMP~
3.Ren7hvdryl-1_~nethvl-2~thio~o~ zoli~iin~4-o~

The title co~ .ld was ~ ,d by the l)~c~lu,~, ~esc~ l in Fy~mr]e 1 using 11.25 g of benzhydryl-isothio~;y~naLe, 7.68 g of s~.;o~ e ethyl ester hydro~h~ . 12 g of triethyl amine, and 200 mL of chlorofo,lll. The title compound was obtained (7.40 g) as an off-white solid, m.p. 139-141 C. Anal. Calcd. for C17 H16 N2 O S: C, 68.89; H, 5.44; N, 9.45. Found: C, 68.92; H, 5.43; N, 9.58. Mass ~e~ (EI, M.+) m/z 296.

FXAMPI ~ 3 l-Methyl-3~ vridin-3-vl)-?-thio~o-i~ zolidin-4-one A mi~ of s~-;o~ e ethyl ester hydrochloride (7.68 g), pyridin-3-yl-isothiocyanate (6.8 g), triethyl amine (10.1 g) and chk"ofo,l" (200 mL) was heated at reflux for 3.5 hours. The solvent was e~/~o ~t~d. The residue was dissolved in ethyl acetate (3Q0 mL) and washed with water (2x200 mL). The organic phase was dried over anhyd,~us m~ .... sulfate. The solvent was e~u a~d. Cryst~lli7~tion from ethyl acetate afforded the title compound (4.1 g) as an off-white solid, m.p. 149-151~
C. Anal. Calcd. for Cg Hg N3 O S: C, 52.16; H, 4.38; N, 20.28. Found: C, 52.16;
H, 4.05; N, 20.06. Mass ~ecL,um (EI, M.+) m/z 207.

~ ~X~MPT,~ 4 3-~5~ oro~ ethoxyvhenvl)~ netlv1-2-thio~o-ilnid~7.olidin-4-one A mixture of sarcosine ethyl ester hydrochloride (7.68 g), 5-chloro-2-methoxyphenyl-i~othiocyanate (10.0 g), triethyl amine (10.0 g) and chlol.ru"ll (lS0 mL) was heated at reflux for 4.5 hours. The llu~ was cooled to W O 97/19932 PCT~US96/19164 le~ ,. The ~l~c~ ~ solid was collecte~l washed with chlc l~ r~ and air dried to give the title ~I~ und (11.8 g) as an off-white solid, m.p. 245-247 C. Anal.
Calcd. forcll Hll Cl N2 O2 S: C, 48.80; H, 4.10; N,10.35. Found: C, 48.42; H, 3.96; N, 10.33. Mass s~ u.n (EI, M.+) m/z 270.
s F.XAMPT,F. 5 3 f3-~hloro-~-lnetllvlDheT~vl)~ nethyl-2-t,hjo~o-i~ 7olidil -4-or e The tide culll~ul-d was pl~al~d by the procedure fles ribe~ in Fy~mrle 1 using 13.2 g of 3-chloro-2-methylphenyl-i~othi~;y~lale~ 11.0 g of ~.;os~c ethyl ester hy(ll~Jcllloride, 25 g of triethyl amine, and 300 mL of chlcl-JfolL,I. Cryst~ 7~tion from diethyl ether arr~.hled dhe title cc,ln~u.~d (15.2 g) as a tan solid, m.p. 122-124~ C.
Anal.Calcd.forC11H11 ClN2OS:C~ 51.87; H, 4.35; N,ll.00. Found: C, 51.96;
H, 4.21; N, 11.05. Mass ~e.;l~.llll (EI, M.+~ m/z 254/256.
lh.X~lVlPI,F, 6 3-(3-(~hloro-4-~ethvlphe~ nethvl-2-thio~o-~ 7olidin-4-ol~e The tide cc,lllpou,~d was ~l~a-~l by dhe procedure ~les~i~l in Exarnple 1 using 18.3 g of 3-chloro-4-,ll~hyl~,he.~yl-isothiocyanate, 15.3 g of sar~osille ethyl ester hydrochloride, 25 g of triethyl amine, and 300 mL of chlclur~ . Cryst~ 7~tion from ethyl acetate afforded dhe title cc,,ll~ulld (14.5 g) as an off-white solid, m.p. 178-180 C. Anal. Calcd. for Cll Hl1 Cl N2 0 S: C, 51.87; H, 4.35; N,11.00. Found: C, 51.89; H,4.20; N, lO.9S. Mass s~)C~,lluln (+FAB, [M+H~mtz 255/257.
~,XAMPI,F 7 3-(4-~hloro-2-1nethvlvhe~ nethyl-2-thio~o~ P~olidi~-4-olle The tide cclll~u-ld was prepared by the procedure ~lescrihe~1 in Example 1 using 9.18 g of 4-chloro-2-methylphenyl-isothiocyanate, 7.68 g of sal-;osi,ic ethyl ester hydrochloride, 12.0 g of triedhyl amine, and 300 mL of chlon)f~ .. Gyst~11i7~tion from diethyl ether afforded the title ccJ.~l~u.~d (7.5 g) as an off-white solid, m.p. 113-115 C. Anal. Calcd. for Cl l H1 l Cl N2 O S; C, 51.87; H, 4.35; N,11.00. Found: C, 51.72; H, 4.17; N, 10.88. Mass spectrum (EI, M.+) m/z 254/256.

CA 02238762 1998-0~-27 W O 97/19932 PCT~US96/19164 ~,X A~P-.F. 8 3~ n-5-yl~-1-meth~l~Z~hioxo-irni~s~oli~in-4-one The tide C~J~ ~UI~t1 was ~ d by the ~vc~lul~ (içscfibe~ in FY~mple 1 using 7.7 g of indan-5-yl-isothio-;yaudle, 6.7 g of Sa-~;OSi~lC ethyl ester hydrochloride, 12 g of triethyl amine, and 300 mL of chlol~rc,~ . Cryst~lli7~tion from ethyl acetate ~f~ol~:led the title c~,m~u-ld (7.9 g) as a tan solid, m.p. 1~8-160~ C. Anal. Calcd. for C13 H14 N2 O S: C, 63.39; H, 5.73; N,11.37. Found: C, 63.30; H, 5.81; N, 11.31.
Mass SPC~,LIUI11 (EI, M.+) m/z 246.

~.X~MPl,~ g 3~ .6-niisoDro,DylDhenyl~ nethyl-2-thioxo~ olidin-4-Qn.

The tide compound was ~ d by the procedure clçscribe~1 in Example 1 using 8.3 g of 2,6-diisopropylphenyl-i~othiocyanate, 5.8 g of sarcosine ethyl ester h5/~r.hlor ~i~., 14.5 g of tnethyl amine, and 200 mL of chlolvfc,~ . ~yst~11i7~tion from diethyl ether/hexane Illi~UI~, afforded the title colll~ulld (6.6 g) as a tan solid, m.p. 174-176 C. Anal. Calcd. for C16 H22 N2 O S: C, 66.17; H, 7.63; N, 9.64.
Found: C, 66.39; H, 7.63; N, 9.59. Mass :~C~ ulll (+FAB, [M+H]+) mlz 269/271.

F.X~IVIP~ ~ 10 3-(2-~,thyl-6-iso~Dro,DylDhenvl~ nethvl-2-thioxo-i~ olidin-4-olle The title coll-~ul~d was ~l~aled by the procedure ~les~i~l in FY~n~ e 1 using 10.25 g of 2-ethyl-6-isopropylphenyl-i~othiocyanate, 7.68 g of sarcosine ethyl ester hydrochloride, 14.8 g of ~iethyl amine, and 200 mL of chlo,vrc""
Cryst~lli7~ti- n from diedhyl Cl~ alle mixture afforded dhe tide compound (8.95 g) as a tan solid, m.p. 132-134 C. Anal. Calcd. for C15 H20 N2 O S: C, 65.18; H, 7.29; N, 10.13. Found: C, 65.11; H, 7.31; N, 10.05. Mass s~et;LIu-ll (PBEI, M.+ ) mlz 276.

~.XAMP~
3 f? ~.thvl-6-methvlDhenvl)~ neth~-2-thiolro-in~ 7~ in-4-one The title com~ulld was ~ d by ~e procedure f~s~ribe~l in Fy~n~rl~ 1 using 8.9 g of 2-edhyl-6-medlylphenyl-i~othiocyanate, 7.68 g of s~u~;o~ule ethyl ester hydrwhlnriflç~ 12.5 g of triethyl amine, and 250 mL of chlor~,rc,llll. Cryst~lli7~tion from diethyl ether afforded the title com~oull.l (7.45 g) as a peach solid, m.p. 106-lQ8~
C. Anal. Calcd. for C13 Hl6 N2 O S: C, 62.87; H, 6.49; N, 11.28. Found: C, 62.52;
H, 6.61; N, 11.29. Mass spectrum (+ESI, [M+H]+) m/z 269/271.
~.X ~MPI ,F 1~
3 (?,_(~,hloro-6.methv~her~yl~ nethvl-2-thio~ro-i~ oli-lin-4-one The tide colll~und was ~d by dle pl~,cellulG ~esçribe~:l in Example 1 using 9.2 g of 2-chloro-6-methylphenyl-isodliocyanate, 7.68 g of sarcosine ethyl ester hydrochloride, 12 g of triethyl amine, and 200 mL of chlor~rclm. Cryst~lli7~ion from ethanol~rr,l~:ledthetitlecolll~ulld (7.1 g) as an orange solid (7.1 g), m.p. 142-14~~
C. Anal. Calcd. for. Cll Hll Cl N2 O S: C, ~1.87; H, 4.35; N,l l.00. Found: C, 51.96; H, 4.26; N, 10.97. Mass ~CCIIulll (EI, M.+) m/z 254.
~.XAMPI ~
3~ .thylD~el~vl~ nethvl-2-thio~o~ oli~lin-4-ol~e The tide ec,l,lpoulld was prepared by the procedure cles~nberl in Example 1 using 16.3 g of 2-ethylphenyl-isothiocy~late, 15.3 g of sal-;osi,le ethyl esterhydroçhlc ncle~ 20.2 g of triethyl arnine, and 300 mL of chlor~,ro~ . The tille compound (20.4 g) was obtained as an off-white solid, m.p. 135-137~ C. Anal. Calcd.
for C12 H14 N2 O S: C, 61.51; H, 6.02; N,11.96. Found: C, 61.11; H, 5.92; N, 11.71. Mass spectrum (EI, M.+3 m/7 234.

W O 97/19932 PCT~US96/19164 li'.X~MP~,h 14 ~vl-3-(2-isonrovvll>he~ t~ljo~co-i~ oli~lin 4 o~

The t}de eu-nl~u-~tl was ~ d by dle ~ 3C~lUIC ~l~.s~bel in FY~mrl~ 1 S using 14.2 g of 2-isopropyl~h~ l-isoll,io~;~allat~" 12.29 g of S~-;OSil.C ethyl ester hyd,ocl-lori~ls, 16.0 g of triethyl amine, and 200 rnL of chlol~fc",ll. Cryst~lli7~-ion from diethyl ether ar~,dcd the title colll~ou,,d (15.9 g) as a peach solid, m.p. 129-131~
C. Anal. Calcd. for C13 Hl6 N2 0 S: C, 62.87; H, 6.49; N, 11.28. Found: C, 62.89;
H, 6.38; N, 11.28. Mass ~l)e~l~u~ EI, M.+) m/z 248.
F,~ ~MPI ,h', 15 3-(~6-nichloro~heny~3-l-nlethvl-2-thio~o-in~ o~ -4-one The tide co-,lpo-l~d was ~ d by the procedure rlescnhe~l in Example 1 using 14.28 g of 2,6-dichlorophenyl-isothiocyanate, 10.75 g of sarcosine edlyl ester hyd~chloride, 14.5 g of triethyl amine, and 200 rnL of chloror~l,ll. C~st~11i7~*-n from diedhyl ether afforded the tide cc,lll~Juund (16.9 g) as a light peach solid, m.p.
207-209 C. Anal. Calcd. for C1o H8 C12 N2 O S: C, 43.65; H, 2.93; N, 10.18.
Found: C, 43.57; H, 2.61; N, 10.14. Mass s~ ulll(EI~ M.+) m/z 274.
h'X ~ MPI ,F, 16 3-(5-~hloro-'~-1nethQ~henyl)-l-etl-vl-2-thio~o-in~ zolidil-4-one 2-Chloro acetic acid (27.5 g) was added pordonwise while stirring to a 70%
aqueous ethyl amine solution (500 mL). The addition was carried over a period of 30 ,..iu,~vs The ~ Lule was stirred at ~llb:t,nt ~I~ .alulG for 18 hours. The llli~Lulc was then e~ ulalc~d to a viscous oily residue (55 g). The crude product con~i~t~l of a 1:1 Lul~ of N-ethyl glycine and ethyl amine hydrochloride. This product mixture was usedwiLlloùL further purific~iQn for the ~l~,p5.li~ of the title compound, in the next 30 paragraph, and for ~ ~aLion of the dtle cc,l~ ounds clescrib~l in Exarnple 17 through Example 42 and in Fx~mrle 58.

A ~ lulc of the cTude N-ethyl glycine (9.23 g), 5-chloro-2-meth~l~h~nyl-isothiocyanate (9.18 g), triethyl atnine (10 g) and chlolur~ (2~0 mL) was heated at reflux for 18 hours. The solvent was e~u~tccl. ~e residue was dissolved in ethylacetate (400 mL) and water (300 mL~. The organic phase was washed with lN HCI
(2x300 mL), then e~,a~,~t~l to dl~llCSS. Purification was achieved through cryst~lli7~tion from ethanol. The tide cc.~ o..~ (7.6 g) was obt;~in~3 as a light pink S solid, m.p. 152-154 C. Anal. Calcd. for. Cl2 H13 Cl N2 0 S: C, 53.63; H, 4.88; N, 10.42. Found: C, 53.36; H, 4.79; N, 10.35. Mass ~ lu-l~ (EI, M.+) m/z 268/270.

F.X~MPI.F 17 3-(Z.6-nichloronhellvl)-l-etllyl-2-thioxo~ olidi~--4-ol~e The tide cun~uul-d was p~ uGd by dle lJlwc~lul~, described in Example 16 using 10.2 g of 2,6-dichlorophenyl-i~othio.iy~atG, 7.4 g of N-e~yl glycine, 10 g of triethyl amine, and 250 rrL of chlu vf~lm. P-- ;r.~ was achieved th~ugh cryst~ ~tion from ethanol. The tide cu~ uul~d (6.5 g) was obtained as a tan solid, m.p. 170-172 C. Anal. Calcd. for. Cll Hlo C12 N2 O S: C, 45.69; H, 3.48; N, 9.69. Found: C, 45.53; H, 3.19; N, 9.62. Mass spectrum (EI, M.+) m/z 288/290/292.

~.XAMPI ,F 1 X
l-F.thvl-3-(4-fll~oroDher~yl3-2-thioxo~ 7olidin-4-or e The tide co-ll~uund was pl~alGd by the procedure clesçrikeA in Example 16 using 7.65 g ûf 4-fluoluph~ yl-isothiocyanate, 9.32 g of N-ethyl glycine, 10 g of ~iethyl amine, and 250 mL of chluluf~ n. PulirlcaLion was achieved through cryst~lli7~tion from ethanûl. The title cc,.ll~oulld (6.6 g) was obtained as a pink solid, m.p. 149-151 C. Anal. Calcd. for. Cll Hl1 F N2 O S: C, 55.45; H, 4.65; N,11.76.
Found: C, ~5.31; H, 4.51; N, 10.82. Mass spectrum (EI, M.+) mtz 238.

~XAMPI .F 19 3-(5-(~hloro-~-~nethoxynher~yl)-1-ethyl-2-thioxo-in ifl~olidin-4-one A l~fi~LulG N-ethyl glycine (9.2 g~, 5-chloro-2-methoxyphenyl-isothiocyanate (10 g), triethylamine (10.1 g), methylene chl~cle (150 rnL) was heated at reflux for 3.5 hours. The ~ LulG was e-/~ldLed tû dryness. The residue coll-~cte~l, washed with W O 97/19932 PCT~US96/19164 hot ethanol and dried. Title co...l o~ 1 (7.6 g) was ob~ d as a creamy solid, m.p.
171-174~ C. Anal. Calcd. for. C12 H13 Cl N2 ~2 S: C, 50.61; H, 4.60; N, 9.84.
Found: C, 50.33; H, 4.50; N, 9.69. Mass 51)~CI1UI~I (EI, M.+) mlz 284/286.

S ~XAMPI.~ 2n I-Ethvl-2-thio~ro-3-(4-tr~ orolnetho~ynhenv~ 7o~ in-4-or~e The tide co~ vund was ~ d by the ~OCe~1U1~ described in FY~n-rl~. 19 using 9.2 g of N-ethyl glycine, 10.9 g of 4-trifluclu~ hoky~llenyl-i~othiocyanate~
10.1 g of triethylamine, and 150 mL of methylene chlor1de P-mfi~tion was achieved by flash cl~u-l~tc,~ hy on silica gel (methylene chloride). Title colll~ou..d (4.6 g) was obtained as a creamy solid, m.p. 116-119 C. Anal. Calcd. for- Cl2 Hl l F3 N2~2 S: C, 47.37; H, 3.64; N, 9.21. Found: C, 47.20; H, 3.50; N, 9.13. Mass spectrum (EI, M.+) m/z 304.
"
F.X~MPI.F 21 3-(~.6-l)ilnethvlphenyl)-1 -ethvl-2-thioxo-imi(l~zoli~ -4-or e The title cvlll~vund was ~ d by the ~luc~lul~ s~ri~ in Example 19 using 9.2 g of N-ethyl glycine, 8.2 g of 2,6-~linwlhylphe.lyl-isothiocyanate, 10.1 g of triethylamine, and 150 mL of methylene chloride. pllrifi~tion was achieved through cryst~lli7~ti- n from ethanol. Title co.lll)uund (2.3 g) was obtained as a white solid (2.3 g). m.p. 128-131 C. Anal. Calcd. for. C13 H16 N2 O S: C, 62.87; H, 6.49, N, 11.28. Found: C, 62.83; H, 6.50; N, 11.25. Mass spectrum (EI, M.+) m/z 248.
~X~MPI,F. ~
1-Ethvl-3-(4-flllorober~ )-2-thio~o-in~ olidil~-4-or~e The title cc,-"~ound was p~,d by the procedure described in Example 19 using 9.2 g of N-ethyl glycine, 8.4 g of 4-flu~ ben~yl-isothiocyanate, 10.1 g oftriethylamine, and 150 rrL of methylene chloride. pnrifi~ cn was achieved through cryst~lli7~tiQn from ethyl acetatelhexane ~"i~CIUlc. Tide compound (4.85 g) was obtained as a white solid, m.p. 73-76 C. Anal. Calcd. for. C12 H13 F N2 O S: C, 57.12; H, 5.19; N, 11.10 Found: C, 56.97; H,5.15; N, 11.06. Mass s~ecL,u~ (EI, M.+) m/z 252.

F.X~MPI ,li. ~
S .l:E~hYl-3-icoh~tyl-2-t-hio~o-i~ 7n~ in-4-one The tide cc,~ 3Oul~d was ~ ,d by the ~ Ce:~lUl~ r1eS( . ;he~l in FyAmrle lg using 9.2 g of N-ethyl glycine, 5.7 g of isobutyl-i~othiocyanate, 10.1 g of triedlylamine, and 150 mL of medhylene chlori~l~ P~;l;cA~ n was achieved by flash 10 cl~l~ull~lugraphy on silica gel (methylene chloride). Tide cc,llllJuwld (2.3 g) was ol~ f~l as an oil. Anal. Calcd. for. Cg H16 N2 0 S: C, 53.97; H, 8.05; N, 13.99.
Found: C, 54.01; H, 8.21; N, 14.00. Mass s~ecllulll (EI, M.+) m/z 200.
li XAMPI,F. ~4 153-~2-(~h~ henyl)-l-ethYl-2-thio~o-i~ olidin-4-one The tide cc,.~ ld was lJl~d by the l ~celul~ described in FYS~ P1C 19 using 9.2 g of N-ethyl glycine, 8.48 g of 2-chl~f~h~nyl-isothiocy~lale, 10.1 g of triethylamine, and 150 mL of methylene chlori~1e p~lrifi~Atinn was achieved dlrough 20 crystAlli7~tion from eth~nol Tide cc,lll~u.ld (3.85 g) was ob~ied as an orange solid, m.p. 142-145~ C. Anal. Calcd. for. Cll Hll Cl N2 O S: C, 51.87; H, 4.35; N, 11.00. Found: C, 51.96; H, 4.26; N, 10.97. Mass spectrum (EI, M.+) m/z 254.

F.X~MPI ,F, '~
251-Ethyl-3-~?-tolyl)-2-thio~o-imif~olidin-4-one The tide compound was ~ )a~d by the procedure described in Example 19 using 9.2 g of N-ethyl glycine, 7.4 g of 2-tolyl-isothiocyallate, 10.1 g of triethylamine, and 150 ~ of methylene chl~ricle Pul.l';c~l;on was achieved through cryst~lli7Atinn 30fr~m ethanol. Title co-~uul-d (3.6 g) was obtained as a Creamy solid, m.p. 105-108~
C. Anal. Calcd. for. C12 H14 N2 0 S: C, 61.51; H, 6.02; N,11.93. Pound: C, 61.22;
H, 5.96; N, 11.89. Mass ~ecL.Illn (EI, M.+~ m/z 234.

WO 97/19932 PCTtUS96/19164 FX~MP~,F '~
l-Ethyl-3-fnal~hth;~len-2-vl)-~-thjoYo-i~ iP~oli~lin-4-o~e The tide co~ oulld was ~.~a.~,d by ~e ~c~lu,~ ~4~sçnl~l in F.Y;.,..1.1e 19 S using 9.2 g of N-ethyl glycine, 9.3 g of 2-naphthyl-i~othin,-y~at~, 10.1 g of trie~ylamine, and 150 mL of methylene chlon~P. pllnfie~tinn was achieved throughcryst~lli7~tiQn from ethanol. Title cv~ vu"d (4.7 g) was cJ~ ed as a light pink solid, m.p. 156-159 C. Anal. Calcd. for. C15 H14 N2 O S: C, 66.64; H, 5.22; N, 10.36 Found: C, 66.69; H,5.24; N, 10.42. Mass ~ccl,ulll f~EI, M.+) mtz 270.
F.X~MPl .F. ~7 3~ hloro-6-methyll~he~yl)- l-ethvl -2-thioxo.in-i-ls 7.01idin-4-one The tide compound was ~&-Gd by the pl~ce~lulG described in F.YZ~ 19 using 9.2 g of N-ethyl glycine, 9.1 g of 2-chloro-6-methylphenyl-iso~iocyanate, 10.1 g of triethylamine, and 150 rriL of methylene chloride. Purification was achieved by flash cl~ tography on silica gel (methylene chloride). C~yst~ tion from ethanol ".led the title cc, ll~uund (5.4 g) as a creamy solid, m.p. 124-126~ C. Anal. Calcd.
for. C12 H13 Cl N2 0 S: C, 53.63; H, 4.87; N, 10.42. Found: C, 53.43; H, 4.79; N, 10.28. Mass spectrum (EI, M.+) mlz 268/270.

li,X~MPI.~. ?.X
thvl-3-f5~ loro-?-methy~ehe~ -thioxo-im~ 7o~ -4-one A llfi~ , of the crude N-ethyl glycine (11.5 g), 5-fluoro-2~ GL~Iylphe,lyl-i~othiocyanate (10.42 g), triethyl amine (12.5 g) and chl~ lln (300 ~) was heated at reflux for 6 hours~ The solvent was evaporated. The residue was dissûlved in ethyl acetate (500 mL) and washed with water (500 mL). The organic phase was e~/a~ldlcd to &~ness. The residue was dissolved in ethanol (50 mL), then diluted with diethyl ether (200 mL). The solution was Salulat~d with hydrogen chlori(le. The ~ Lu~c was filtered. The solid was discarded. The filtrate was evaporated to dryness. The residue was dissolved in diethyl ether (300 rnL) and washed with water (200 mL). The organic phase was dried over anhydrous sodium su}fate and e~ d to dryness.
C~yst~lli7~tion from ethanol afforded the title compound (6.5 g) as a pink solid, m.p.

CA 02238762 l998-05-27 98-100 C. Anal. Calcd. for. Cl2 H13 F N2 0 S: C, 57.13; H, 5.19; N, 11.10.
Found: C, 56.88; H, 5.17; N, 11.05. Mass speellull~ (EI, M.+) m/z 252.

l;,XAN~IPI,~. ?g 3-f2-6-niiso~roDvlDherlv~ -ethyl-2-thioxo-~ 7o~ n-4-one Ihe tide c;~ oulld was pn;pa-~d by ~e yluc~lu~ e~ihe~l in Example 16 using 21.9 g of 2,6-diisul,-v~ylphenyl-isothiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 300 rnL of chlulofc~ . Pimfi~tion was achieved through 10 crys~lli7~tion from ethanol. The tide compound (8.2 g) was obtained as light yellow solid, m.p. 159-161 C. Anal. Calcd. for. C17 H24 N2 O ~: C, 67.07; H, 7.94, N, 9.20. Found: C, 66.92; H, 8.03; N, 9.13. Mass spe~um ~BEI, M.+) m/z 304.
F'.XAMPl ,~, 3~
l ~hyl 2 thioxo 3-(2 trifl~lorome~t.~erlyl)-i~ 7.olidin-4-ore.

The tide comyoulld was plCp~ d by dle ~ lul., described in FY~mrl~P 19 using 9.2 g of N-edlyl glycine, 10.2 g of 2-(llinuu~ yl)-phenyl-isothiocyanate~
10.1 g of triethylamine, and 150 mL of Illell~ylene chloride. The residue was fur~er 2û pnrifiPr3 by flash clllu~ o~rhy on silica gel (me~ylene chloride). ~ysts~ 7~t~
i~om ethanol afforded ~e title compound (2.7 g), m.p. 82-85 C. Anal. Calcd. for.C12 Hl 1 F3 N2 O S: C, 50.00; H, 3.85; N,9.72. Found: C, 50.00; H, 3.61; N, 9.61 Mass ~J~Il Ulll (EI, M.+) m/z 288.

li XAMP~,~ 31 l-Ethyl-3-(?-ethyl-6-iso~roDylvhelv1)-2-thioxo-i~ olidir-4-ol-e The title compound was pl~ d by the procedure described in Example 28 using 2û.5 g of 2-ethyl-6-isu~3,o~yll,hc.~yl-isothiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 3ûO mL of chlc,lorv~ . Purification was achieved by flash cl,lvll~Lugraphy on silica gel (5-lû % ethyl acetate in hexane). Cry~t~11i7~ti-n from diethyl ether/hexane afforded pure title conl~uulld (7.5 g) as a white solid, m.p. 77-79~

W O 97tl9932 PCT~US96/19164 C. Anal. Calcd. for. C16 H22 N2 0 S: C, 66.17; H, 7.64; N, 9.65. Found: C, 66.12;
H, 7.77; N, 9.69. Mass Sl)CCllulll (EI, M.+) m/z 290.

~.X ~MPI ,F. ~2 l.F',tl~ 3-f2-etiv1-6-~netll.,ylpheru1~-2-thioxo-i~ 701i~1in-4-one The tide co~ ound was ~.~al~d by dhe procedure desc~ in FY~mrlt-. 28 using 17.7 g of 2-ethyl-6-methyl~he.lyl-i~othiwyanate~ 18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 300 rnL of chlc"orc,lll,. The residue was further purified by 10 flash chr~m~tography on silica gel (20 % ethyl ~etate in hexane).The title col.l~oulld was obtained (8.6 g) as a light peach solid, m.p. 82-84~ C. Anal. Calcd. for. C14 Hlg N2 O S: C, 64.09; H, 6.92; N, 10.68. Found: C, 64.27; H, 7.04; N, 10.60. Mass spectrum (EI, M.+) m/z 262.

~XAMPI h 33 3-f~ loro-4-lnethylvhel~yl)-l-ethyl-2-thioxo-i~ 7 lidin-4-or e The tide col~ ul~d was ~.e~,d by dhe procedure described in Example 28 using 18.3 g of 2-chloro-4-methylphenyl-i~othi-~cy~ e, 18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 300 mI, of chlol~fo,lll. Cryst~11i7~tion from ethyl acetate afforded dhe title compound (5.8 g) as a peach solid, m.p. 126-128~ C. Anal. Calcd.
for. C12 H13 Cl N2 0 S: C, 53.63; ~I, 4.88; N, 10.42. Found: C, 53.50; H, 4.76, N, 10.28. Mass spectrum (+FAB, [M+H]+) m/z 269/271.

~.Y~ Dle 34 1 -~,thyl-3-rl-(4-fl~oro~hellyl)-ethyll-2-thioxo-imid~7~ -4-ol-e The tide compound was prepared by dhe procedure described in E~"~lc 16 using 18.1 g of 1-(4-fluorophenyl)-ethyl-isothiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 300 rnL of chlor~ro.lll. Cryst~lli7~tic-n from ethyl acetate arro,.lcd dhe tide co~ ound (8.8 g) as a light yellow solid, m.p. 93-95 C. Anal.Calcd. for. C13 Hls F N2 O S: C, 58.63; H, 5.68; N, 10.52. Found: C, 58.69; H, 5.64; N, 10.58. Mass ~)c~ ulll (EI, M.+) m/z 266.

W O 97/19932 PCT~US96/19164 ~,X A M P~ ~ 35 3-(?~4~nichlorovhenyl)-t-ethv~ thio~ro~ lin-4-one The ti~e colll~vund was ~ ~Gd by the ~1~C~G ~SÇ~he~ in FY~nnr1e 16 using 20.4 g of 2,3-dichlor~lcnyl-i~othiocyanate,18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 300 mL of chl(,l~)ro ~ tifir~lion was achieved by flash ch~ o~rhy on silica gel (20 % ethyl acetate in hexane) The ti~e co,,.~oulld (8.8 g) wasobtainedasalightpeachsolid,m.p. 144-146 C. Anal. Calcd. for. C11 Hlo C12 N2 O S: C, 45.69; H, 3.49; N, 9.69. Found: C, 45.81; H, 3.40; N, 9.58. Mass D~c~Llulll(cI~[M +H1+)n~Z Z89/291/293.

~.X ~ M P-,F, 36 t~yl-3-vh~hvl-2-thio~o-i~ olidin-4-one The title c~ ou-ld was p-~pdl~,d by the p~c~lure described in FY~mrle 16 using 16.3 g of ~h--lel~lyl-isOthiO~;yanaLe~l8.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 300 mL of chlororc. ---. p~lr~fic~tion was a l.ie~cd by flash cl~lvn~al~graphy on silica gel (20 % ethyl acetate in hexane) The title co---~ou--d (lS.0 g) was obtained as an off-white solid, m.p. 66-68 C. Anal. Calcd. for. C13 H16 N2 O S: C, 62.87; H, 6.49; N, 11.28. Found: C, 63.03; H, 6.49; N, 11.32. Mass ~e~u~ EI, M.+) m/z 248.

~.X ~P~,~. 37 3-f~3~n;rnet~YI~hel~V~ ethVI~2-th;O~O~;rn;~ OI;d;n~4~OI~e The title compound was prepared by the yl-~ce~ e described in Example 16 using 16.3 g of 2,3~imethylphenyl-isothiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 250 mL of chloro~c, -ll. C~ystsl11i7~1;nn from ethanol afforded the titlecc,.. pou.ld(10.3g)asalightpink solid, m.p. 120~121 C. AnaI. Calcd. for. C13 H16N20S:C,62.87;H, 6.49; N, 11.28. Found:C, 62.72; H, 6.44; N, 11.47.
Mass spectrum (EI, M.+) m/z 248.

W O 97/19932 PCT~US96/I9164 ~.XAMP~ ~. 3g 3 ~?.. 4.1-imetl~ylphe~ et~yl-2-thioxo-in~ 7.oli-1in-4-orîe The tide co-,l~wld was p,~p~d by the ~ c~lu~ les~ - ;l~l in RY~mrlt- 16 S using 16.3 g of 2,4-dil~ yll)}.~,n~ sothioe~&le~ 18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 250 mL of chlon,f~ . Cryst~ ti-)n fiom ethanol ~rr,,~ .1 the title coll~c ulld (10.8 g) as a light peach solid, m.p. 161-162 C. Anal. Calcd. for. C13 H16 N2 O S: C,62.87; H, 6.49; N, 11.28. Found: C, 62.63; H, 6.45; N, 11.17. Masss~ unl ~EI, M.+) m/z 248.
F.X ~ M Pl,~, 39 3 f~ nethvlDhenvl)-l-ethyl-2-thiolro-ilnid~7oli~lin-4-one The title cc,-ll~ou.,d was ~,~ed by the ~ ce(lur~ descnbed in Example 16 using 16.3 g of 2,5-dimethylphenyl-isothiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 250 mL of chlo vÇ~ l,l. Cryst~lli7~ion from ethyl acetate arru.~led the tide colll~ound (10.6 g) as an off-white solid, m.p. 176-178~ C. Anal. Calcd. for.
C13 H16 N2 O S: C,62.87; H, 6.49; N, 11.28. Found: C, 62.70; H, 6.46; N, 11.27.
Mass ~ lUIll (EI, M.+) m/z 248.
l~X~MPT.F 40 I-Ethvl-2-thioxo-3-(2.4-i-trimeth~2he~ imid~7olidsn-4-one The tide compound was y~ y the procedure ~lescri~ed in Example 16 using 17.7 g of 2~4~s-tli~ hylphenyl-isothiocyanate~ 18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 250 mL of chlol~Ç~ . Cryst~lli7~1irn from ethanol afforded thetitle compound (15.3g) as an off-white solid, m.p. 162-164~ C. Anal. Calcd. for.
C14 Hlg N2 O S: C,64.09; H, 6.92; N, 10.68. Found: C, 64.21; H, 6.93; N, 10.80.
Mass s~e.;~l um (EI, M.+) m/z 262.

CA 02238762 l998-05-27 W O 97/19932 PCT~US96~19164 ~.XAl~lPl.li 41 l-Ethyl-3-f?-i~ol~roDvll~he-~yl)-?-thioYo-imi~ oli-lin-4-one The tide cc,~p~und was ~ d by the procedure ~les~ ;l~l in FY~mr1lo 16 using 15.42 g of 2-iS<*J~ he~ ;~ y~l~al~l6.05 g of N-ethyl glycine, 12 g of triethyl arnine, and 200 ~ of chlor~Ço~ . P!..;r;.~,;;on was achieved by flash ch-~,mal(,~d~hy on silica gel (5-20 % ethyl acetate in hexane) C~yst~ tioll fromethanol afforded the tide con-~ollnd (9.8 g) as a white solid, m.p. 125-127~ C. Anal.
Calcd. for. Cl4 Hlg N2 0 S: C, 64.09; H, 6.91; N, 10.68. Found: C, 64.l9 H, 6.93;
N, 10.71. Mass spectrum ~EI, M.+) m/z 262.

F'.XAMPI.F 42 1 E~hy1-3-(2-et~y1Dherly1~-2-thio~ro i~il~zo1idin 4 o-e The title co~ o~lnd was prepared by the ~ ce lul-, described in Example 16 using 16.3 g of 2-edlylphenyl-i.cothi-~cyanate, 18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 200 mL of chlol~.Ç{.llll. Pnrifi~tiQn was achi~,vcd by flashcL~ graphy on silica gel (5-10 % ethyl acetate in hexane) ~yst~l1i7~tion from diethyl ether arrol~lcd the tide cc..~vulld (9.12 g) as a white solid, m.p. 71-73~ C.
Anal. Calcd. for. C13 H16 N2 0 S: C,62.87; H, 6.49; N, 11.28. Found: C, 62.81; H, 6.43; N, 11.17. Mass spectrum (EI, M.+) m/z 248.

h XAMPI,F. 43 3-(5-Chloro-2-methyl~henyl)-l-Dhenyl-~--thio~ro-i~ zolidin-4-one 2~
A ~ Lul., of N-phenyl glycine ethyl ester (8.95 g), 5-chloro-2-methylphenyl-i~othio~iy~ale (9.18 g), and chlol~rcll-1 (200 mL) was heated at reflux ~or 24 hours.
The solvent was e~ay~ ed. The residue was cryst~lli7PA from ethyl acetate~exane Illi~lUlG. The solid was collPctt~l and dried to give 17.2 g of 2-[3-(5-chloro-2-Illclllylyhenyl)-l-phenyl-thioureido]-acetic acid ethyl ester as a white solid, m.p. 148-150~ C. Anal. Calcd. for. Clg Hlg Cl N2 ~2 S: C, 59.~8; H, 5.28; N, 7.72. Found:C, 59.79; H, 5.38; N, 7.65. Mass spectrum (EI, M.+) mtz 262/264.

W O 97/19932 PCT~US96/19164 A ~ , of 2-[3-(5-chloro-2-~ ,Ll~ h~ yl)-l-phenyl-thioureido]-acetic acid ethyl ester (9.5 g), triethyl amine (1 mL), and ethanol ~150 rnL) was heated at reflux for 2 hours. The mixture was ~ r~ Atr~l to one-half volume and cooled to ambient t~ p~ ,. The solid was collect~ and aLr dried to give the tide col~c,und (6.1 g) as S an off-white solid, m.p. 168-170 C. Anal. Calcd. for. Cl6 H13 Cl N2 0 S: C, 60.66;
H, 4.14; N, 8.84. Found: C, 60.81; H, 4.16; N, 8.81. Mass ~.~euLl.~ll (EI, M.+) m/z 316/318.

FX ~MPT .lh 44 3-f3-(~hloro-2-lnethvlDhel~yl)- l-Dhenyl-2-thio~o-in~ 7.oli/~in-4-one A llli~lUIG of N-phenyl glycine ethyl ester (8.95 g), 3-chloro-2-methylphenyl-isc,~lio~;yana~e (9.18 g), and chlon~fclll~ (200 mL) was heated at reflux for 18 hours.
The solvent was e~,apc,lated to dryness. The residue was mixed with ethanol (150 mL), 15 and tnethyl amine (3 mL). The mixture was heated at reflux for 3 hours. The solvent was e~/d~ulàtGd. The residue was dissolved in ethyl acetate (300 mL) and washed with lN HCl (2x200 mL), then with water ~200 mL). The organic phase was dried over anl.y~uusm~? ..e~ l.. sulfateandevaporatedtodryness. The residue was treated with diethyl ether. The solid was coll~t~ by fil~*t~n and air dried to give the titlecoll-~oul-d (5.3 g) as an off-white solid, m.p. 154-156 C. Anal. Calcd. for. C16 H13 Cl N2 O S: C, 60.66; H, 4.14; N, 8.84. Found: C, 60.48; H, 4.05; N, 8.76. Mass ~)~;11 Uln (+FAB, [M+H]+) m/z 317/319.

li',X~MPl,~, 45 3-(5-Chloro-2-~nethvlphelvl)-1-isoDropyl-~-tl~ioxo-i~ olidin-4-one 2-Chloro acetic acid (69.0 g) was added portionwise while stirring to a iso~lu~yl amine (431.5 g). The additiûn was calried over a period ûf 30 ~hl~ltes. The llliX.~WG was stirred at r~ t ~ UlG fûr 18 hours. The excess iso~lu~yl amine30 was e~ ol~,d leaving a viscous clear oil (182.0 g) which soli~lifi~ upûn standing.
The crude product c~n~i~t~ of a 1:1 mixture ûf N-isûpropyl glycine and isopropylamine hydrochlo~i-le. This product mixture was used without further purification for the ~ ion of the tide cu~ )ound, in the next paragraph, and for pl~lion ûf dle tide co-l-~ul-ds described in Example 46 through Example 52.

CA 02238762 l998-05-27 W O 97/19932 PCT~US96/19164 A ~ lul~ofdlecrude N-is<~ ylglycine (21.2 g), 5-chlor~2-~ yl~h~,.~1-i~othi-~cyanate (18.3 g), triethyl amine al-0 g) and chlolufc, ll~ (300 mL) was heated at reflux for 4 hours. The solvene was ~,V~ ~d. The residue was dissolved in ethyl acetate (400 rnL) and water (300 mL). The organic phase was washed with 2N HCl (2x300 mL), then with water. The organic phase was dried over anhy~lrvus m~
sulfate and e~ ted to dryness. Cryst~lli7~tinn from ethanol afforded the tide coll~und (15.4 g) as a peach solid, m.p. 142-144 C. Anal. Calcd. for. C13 H1s ClN2 O S: C, 55.21; H, 5.35; N, 9.91. Found: C, 55.07; H, 5.20; N, 9.82. Mass 0 ~i~C~,Llul~ (+FAB, lM+H]+) m/z 283/285.

FX ~MPl ,F 46 3-(?..6-T)imethvlehenyl)-l-isoDro~yi-?-thio~o-imi~l~znlidin-4-or~e The tide compound was ~ d by the ~locelu,~ escr~ in FY~n~rle 45 using 16.3 g of 2,6-dimethylphenyl-isothiocyana~e, 21.2g of N-isu~,ro~yl glycine, 21.0 g of ~iethyl amine, and 300 mL of chlol~)rcllll. Cryst~11i7~ticn from ethanol afforded the title co~ l (12.9 g) as a white solid, m.p. 135-137~ C. Anal. Calcd.
for. C14 H1g N2 0 S: C, 64.09; H, 6.92; N, 10.68. Found: C, 63.99; H, 6.72; N, 10.67. Mass spectrum (+FAB, [M+H~+) m/z 263.

FX~MP~ ~ 47 3~ .6-T)iisoDro~ylDhel~vl)-l-isoDroDYI-2-thio~ro-imid~:olidill-4-ol-e The ti~e cc~ uul,d was ~ ,d by the ~J vce lu,., des~ihe~l in Example 45 using 21.9 g of 2,6-diis~l~l,yl~hcnyl-isothiocyanate, 21.2 g of N-isopropyl glycine, 21.0 g of triethyl amine, and 300 mL of chl~ ,fc..l". Cryst~lli7~ti-n from ethanol affordedthetitleco-~l~und (11.7 g) as a white solid, m.p. 175-177 C. Anal. Calcd.
for. C1g H26 N2 O S: C, 67.88; H, 8.23; N, 8.80. Found: C, 68.03; H, 8.09; N, 8.81. Mass spectrum (+FAB, [M+H]+~ m/z 319.

W O 97/19932 PCT~US96/19164 ~.X ~ M PT.~, 48 3.(4-Flmoronhenvl)-l-i~oDrol~yl-?,-thioYo-in~ oli~in-4 o~ e The tide colllyoLIl-d was y~ d by the l~luce~ , described in FY~mrl.o 45 using 15.3 g of 4-lluu ~phcl~yl-i~othi~cyanate, 21.2 g of N-iso~>loyyl glycine, 21.0 g of triethyl amine, and 300 mL of chlol~rc llll. Cryst~lli7~ti- n from ethanol afforded the title colllyc,u-ld (12.6 g) as a peach solid, m.p. 184-186~ C. Anal. Calcd. for. C12 H13 F N2 O S: C, 57.12; H, 5.19; N, 11.10. Found: C, 56.98; H, 5.09; N, 11.06. Mass ~CCIIUII1 (+FAB, ~M+H]+) m/z 253.
F'X A MPl ,F' 49 3-(In-l~n-S-yl)-l-isovrovvl-2-t~ioxo-ilni-1~7.oli~ -4-one The ti~e cc,lllyoulld was yl~y~u~d by the procedure described in Example 45 15 using 17.5 g of indan-5-yl-isothiocyanate, 21.2 g of N-isoyloyyl glycine, 21.0 g of triethyl amine, and 300 mL of chloroform. Cryst~l1i7~ti~n from ethanol arrc,l~led the title collll,uulld (9.9 g) as a white solid, m.p. 178-180 C. Anal. Calcd. for. Cls Hlg N2 O S: C, 56.66; H, 6.61; N, 10.21. Found: C, 56.70; H, 6.67; N, 10.22. Mass ~7~eCLlUIII (EI, M.+) m/z 274.
FX~MPI ~ 50 3-(2-~.tlv1-6-nlethvlphenyl)-1 -iso~ro~yl-2-thio~o-imi~olidin-4-one The title compound was y~d by the procedure describe~l in Fy~mpl~o 45 25 using 17.7 g of 2-ethyl-6-lllcLllylyh~,nyl-isothiocyanate,21.2 g of N-isc,yl~oyyl glycine, 21.0 g of triethyl amine, and 300 mL of chloroform. Cryst~lli7~fifn from ethanolarr~ ed the title ccllly.~ulld (13.0 g) as a light yellow solid, m.p. 132-134~ C. Anal.
Calcd. for. Cls H20 N2 0 S: C, 65.18; H, 7.29; N, 10.14. Found: C, 65.06; H, 7.37; N, 10.20. Mass spectrum (EI, M.+) mtz 276.

F'X~MPI,F'. 51 3,f?,.1;,thvlDh~nvl)-l-isorroDvl-'~-thiolro-i~nirl~7~ 1in-4-one The tide co~ uu-~d was ~ d by the lJl.,ce~lu.~, ~lesç~iheA in F~ e 45 S using 16.3 g of 2 ~lhyl~)he"yl-isothiocyanate, 21.2 g of N-isc~l~yl glycine, 21.0 g of triethyl amine, and 300 mL of chlorurv.,l,. Cryst~lli7~ti- n from diethyl ether ~rul~l~d the tide compound (6.8 g) as a white solid, m.p. 103-105 C. Anal. Calcd. for. C14 H1g N2 O S: C, 64.09; H, 6.92; N, 10.68. Found: C, 64.08; H, 6.92; N, 10.62.
Mass ~ Ull~ (EI, M.+)m/z 262.
~.X ~ M PT,F, 5?
1-Isol?ro~yl-3-(~ isonro~vlnhenyl)-2-thioxo-imirlszoli~ -4-one The title coll~ u--d was pl~,,J~d by the procedure ~lescn~l in Example 45 using 10.0 g of 2-is~.ul,yll)he.lyl-isothiocyanate, 11.9 g of N-isopropyl glycine, 12.0 g of triethyl amine, and 200 mL of chlol~r~ l. Cryst~lli7~tinn from ethanol afforded the title co---~,ound (6.8 g) as a light pink solid, m.p. 112-114~ C. Anal. Calcd. for.
C15 H20 N2 O S: C, 65.18; H, 7.29; N, 10.13. Found: C, 65.51; H, 7.25; N, 10.32.Mass s~ u-.- (EI, M.+) m/z 276.
F.X~MPT.~. 53 1-Psen7~l-3-(4-b~tvl~henvl)-?-thioxo-i~ olidin-4-olle A mixture of N-benzyl glycine (8.7 g), 4-n-butylphenyl-i~othiocyanate (8.55 g), triethyl amine (5.5 g) and chk, ~Çu~ (150 rrL) was heated at reflux for 5 hours.
The solvent was e~alx, ~.,d. The residue was dissolved in ethyl acetate (300 mL) and water (2x200 mL). The organic phase was dried over anhydrous m~ne~ m sulfate and eva~ ~led to dryness. Cryst~ 7~tion from ethyl acetate afforded the title co--~ ulld (11.4 g) as an off-white solid, m.p. 149-151 C. Anal. Calcd. for. C20H22 N2 O S: C, 70.97; H, 6.55; N, 8.28. Found: C, 70.81; H, 6.76; N, 8.32. Mass :~u;l~ulll(EI~ M.+) m/z 338.

F,X ~ M P~ 54 1.Rntvl_3.f5.chloro-2,methvlph~nyl) 2_thioxo ilnid~701idin_4 or~e 2-Chloro acetic acid (47.3 g) was added ~u~ wise while stirring to a n-butyl S amine (500.0 g). The ~ li*~ n was carfied over a period of 30 .~ t~ s. The ~ ule was s~irred at ~~~' t~ , for 18 hours. The excess n-butyl amine was GVal~Uldt~ leaving a viscous clear oil (120.0 g) which soli~lifiç~l upon st~n-ling The crude product con~i~te~l of a 1~ Lulle of N-butyl glycine and butyl amine hy&u~;hlorirle This product Il~i~lul~, was used will~oul further ~ ;r~ on for the l~l~a~ j lion of the tide cc)lllyuulld, in the next paragraph, and for ~ uaLion of the title co ll~uunds ~l~sçriheA in Example 55 and Example 56.

A l~ Lul~, of N-butyl glycine (12.0 g), 5-chloro-2-methyl~hc.,yl-i~othiocyanate (9.15 g), triethyl amine (12.0 g) and chlc,lur~,l.ll (200 rnL) was heated at reflux for 5 hours. The so}vent was e~d~uldlt;d. The residue was treated with diethyl ether (400 mL). The mi~clul~ was filtered. The solid was washed with diethyl ether then discarded.
The filtrate was e~d~uldt~ to dryness. Cryst~lli7~;on from ethanol afforded the tide co~ ou"d (6.0 g) as a tan solid, m.p. 102-103 C. Anal. Calcd. for. C14 H17 Cl N2O S: C, 56.65; H, 5.77; N, 9.44. Found: C, 56.41; H, 5.97; N, 9.36. Mass spectrum (EI, M.+) m/z 296/298.

h'X ~MPI ~ 55 I-R~Ityl-3-(4-fll~oroDhenvl)-2-thio~o~ 7olidin-4-or e The tide colll~uul-d was pl~alGd by dhe procedure described in Example 54 using 7.7 g of 4-fluolvphenyl-isothiocyanate, 12.0 g of N-butyl glycine, 15.0 g o triedhyl amine, and 250 mL of chlolvrolll,. Cryst~lli7~tion from ethanol afforded the tide cu..l~und (5.9 g) as an off-white solid, m.p. 92-93~ C. Anal. Calcd. for. C13 H1s F N2 O S: C, 58.62; H, 5.68; N, 10.52. Found: C, 58.23; H, 5.65; N, 10.56.
30 Mass spectrum (EI, M.+) m/z 266.

W O 97/19932 PCT~US96/19164 '~.X~MPl,h', 56 1_RI~tvl~3-(2~chloro-6-methyll~henyl3-~-thio~o-ir~id~ol~ n-4-one The ti~e cc~ d was ~ d by the pl~ce~ les~ihe~l in E~ll~le 54 S using 6.5 g of 2-chloro-6-1lwlllyl~hen~1-isothiocyanate, 8.5 g of N-butyl glycine, 10.0 g of triethyl amine, and 150lIlL of methylene ch~ e. p~ fic~tion was achieved byflash cl-l...~ ~aphy on silica gel (methylene chlori-1e). ~yst~11i7~tinn from ethanol afforded the title colll~,ulld (3.85 g) as a light pink solid, m.p. 97-100~ C. Anal.
Calcd. for. C14 H17 Cl N2 O S: C, 56.65; H, 5.77; N, 9.44. Found: C, 56.45; H, 5.67; N, 9.33. Mass SL)e~ ulll (+FAB, [M+H]+) m/z 297.

F'.X ~MPl ~ 57 3-(4-t-R~tvlDl~envl~ nethvl-~-thio~o-imifl~7olidin-4-olle A nli~ of sarcosine ethyl ester hydrochloride (7.68 g), 4-t-butylphenyl-isothiocyanate (9.6 g), triethyl amine (10.1 g) and chloloÇc,llll (250 mL) was heated at reflux for 3 hours. The Illi~ was cooled to ~l~L,~ ture, washed with 2N
HCl (2x200 mL), d~en with water (200 mL). The organic phase was dried over anhydlous m~.. csi.. sulfate and e~ d to dryness. The residue was cryst~lli7~
from ethanol to give the title co~ ou,~d (9.9 g), m.p. 156-158~ C. Anal. Calcd. for C14 Hlg N2 O S: C, 64.09; H, 6.91; N,10.68. Found: C, 63.83; H, 7.15; N, 10.53.
Mass *,eell Ulll (EI, M.+) m/z 262.

l~.X~MPT,h, S8 l-h'~thyl-3-(2-metl~ylsl~lf~yl~he~yl)-2-thio~o-ilnidazol~ n-4-one A I~ lule of N-ethyl glycine (9.23 g), 2-(methyl~io)-phenyl-iso~iocy~
(9.1 g), triethylarnine (10.1 g) and methylene ehlori~l~ (150 rrL) was heated at reflux for 3 hours. The llfi~ was evaporated to dryness. The residue was recryst~11i7PAfrom ethanol to give the title cc,lll~und (6.5 g) as a creamy solid, m.p. 128-131~ C.
Anal. Calcd. for. Cl 2H l 4N2S2O: C, 52.11; H, 5.30; N, 10.52. Pound: C, 52.28; H, 5.26; N, 10.54. Mass s~e~ ,m (EI, M.+) m/z 266.

W O 97/19932 PCT~US96/19164 -3~-T~.X ~ M PT,~, 59 llvl-3-(~ methLvlnhenv~ -th~Q-inni~7.ol~ -4-one Chloroacetic acid (27.5 g) was added portionwise over 5 ~ s to a cooled io~ of allyld~ e (114 g) in water (100 mL). The reaction mixture was sti~red at ~ml- t~m~,alulefor48 hours. The l~fL~ul~ was then e~ .t~1 to a viscous oily residue (35 g). The crude ~ U~;L consisted of a 1~ UIe of N-allyl glycine and allyl amine hydrochloride. This l r~lucL llll~lUI~, was used without further p~ tir~n for the p~ ~alion of the tide c~ ul,d, in the next paragraph, and for ~G~ ;c n of the title c~mro~mrl ~çsc~ in F.Y~mrl~ 60.

A l~ lUl~ of N-allyl glycine (17.4 g), 2,6-din~lLllyl~hcl~yl-i~othiocyanate (20 g), triethylamine (20.2 g), and methylene chlcri~le (150 mL) was heated at reflux for 3 hours. The l~,a~lion l~ lUle was ev~ted to dryness. The residual gum was dissolved in diethyl ether, then treated with etheral hydrogen chloride. A white solid formed. The solid was filtered and discarded. The filtrate was con~entratP~l to a residue. The residure was cL~ aL~ r~ on silica gel (CH2C12) to give tide co,ll~ou,-d (5.2 g) as an orange solid, m.p. 43-46 C. Anal. Calcd. for. C14 Hl6 N2 OS: C, 64.59; H, 6.19; N, 10.76. Found: C, 64.52; H, 6.08; N, 10.66. Mass s~ u~-l (EI, M.+) m/z 260.

T~.X~ IPT ~ 60 1-AIIvl-3-~5-chloro~2-1nethylDhellvl~-~.-thio~o-i~ olidin-4~one A llfi~clul~ of N-allyl glycine (17.4 g), S-chloro 2-medlyll,henyl-isothiocyanate (20.1 g), triethylamine (20.2 g), and methylene ehlQri-le (150 rnL) was heated at reflux for 2 hours.
The reaction mixture was ev~ te~l to dryness. Plmfi~iort was achieved by flash 30 chr~ graphy on silica gel (methylene chloride). Recrys~lli7~sion from Hexane-EtOAc afford the title co,lll)u,ll~d (4.8 g) as yellow solid, m.p. 106-109~ C. Anal. Calcd. for. Cl3 H13 N2 0 Cl S: C, 55.61; H, 4.67; N, 9.98. Found: C, 55.45; H, 4.56; N, 9.72. Mass ~cL.u (EI, M.+) m/z 280.

W O 97/19932 PCT~S96/19164 ~,X ~ M Pl.T~, fil 3 (2,6,-limethvlvhenvl~ furov-2-vnvl)-~,-thjoxo-in~ 701i~1in 4-one To a cooled sollltinn of ethyl l~ u..~ (37.6 g) in diethyl ether (75 mL), S was added ~lu~ylamine (25 g). The 11~ U1G was sdrred for 3 hour at 0-5 C. T~e ,~;~ivn ~ was raised to ~ nt te~ c,~" and the sdrring c~ni.~ l for 18 hours. A solid formed~ The sol;d was filtered and discarded. The filtrate wasev~ul~ to dryness to give crude dtle co~ uul~d (30.1 g). The crude product was used without further purificadon for the ~.~a.~Lion of the dtle co npou..d, in the next 10 paragraph, and for plGp~u~-on of the dtle co~ vu..ds ~lescrihed in Fy~mrle 62 and Ex~mple63.

A llli~lUl~, of ethyl N-pl~al~yl~mino~et~t~ (14.1 g), 2,6-dimethylphenyl-isothiocyanate (16.3 g3, L~it~ la--~ l~ (10.1 g), and methylene chloride (lS0 mL) was 15 heated at reflux for 3 hours. The reaction mixture was cooled to ' ~ lel~
washed with lN HCl (100 mL), then with water. The organic layer was s~a~ d, dried over anhydr~us m~ nf~ m sulfate, then evaporated to dryness. The residual oil wasl.;l~..i.k~lwithhexane.Thesolidwasc~-llect~fl by fîltration. Recry~t~lli7~nn from h~ t-EtOAc afforded the ~de co,-~oulld (12.5 g) as yellow solid, m.p. 117-121~ C.
Anal. Calcd. for. C14 Hl4N2s2 O: C, 65.09; H, 5.46; N, 10.84. Found: C, 65.23;
H, 5.43; N, 10.88. Mass ~.~e-;~.wll (EI, M.+) m/z 258.

~,XAMPT.~ 62 3-(5-chloro-~ nethvlphenyl)-l-(DroD-2-vrvl~-2-thioxo i~ 70lidi 4-one A ll~ WG of ethyl N~ pal~,yl~.i.)o~el.~e (7.0 g), 5-chloro-2-.l~.,~I.yl~henylisothi~;yal a~ (9.2 g), Il;c~lyl&l.lil,c (5.0 g), and methylene chloride 30 (100 niL) was heated at reflux for 3 hours. The reaction I~ Ul~; was cooled to ~...I-ie..t le.ll~)~.d~ul~, washed with 1 N HCl (50 mL), then with water. The organic layer was dried over anhyd-~u~ m~ sulfate, then e~u.~led to dryness. The residual oil was ~ ~ with hexane. The solid was coli~c~e{l by filtration.
Recryst~ili7~tion from EtOAc affoTd the title coll~ou~ld (5.1 g) as yellow solid, m.p.

131-134 C. Anal. Calcd. for. C13 Hll N2 O Cl S: C, 56.01; H, 3.98; N, 10.05.
Found: C, 55.90; H, 3.77; N, 9.92. Mass spe~cL~ul-~ (EI, M.+) m/z 278.

h'XAMPI ,li' 63 ~ ~ ~hloro~2-nletl~yl,Dhel~vl~ rDron-? yr~l)-2-thio~ro~ olirlin-4-one A ~llixlul~ of ethyl N-y~u~f~ minc~'e~t~ (10.0 g), ~chloro-2-l~lhyly~.lyliso~hio~y~laLe (12.9 g), triethylamine (7.1 g), and methylene chloride (150 rliL) was heated at reflux for 3 hours. The reaction IniXIUl~, was cooled to ~mhi~n~ nly~alLu~" washed with 1 N HCl (100 mL), then with water. The o~ganic layer was dried over anhydl~us m~ h~I sulfate, then evaporated to dryness. The residual oil was LliLul~l with hexane. The solid was ccllp~teA by fil~T~tion Recryst~11i7~ti~n from H~ tOAc afford the title co~ uu~ld (5.2 g) as yellow solid, m.p. 99-102 C. Anal. Calcd. for. C13 Hll N2 O Cl S: C, 56.01; H, 3.98; N,10.05. Found: C, 55.61; H, 3.83; N, 10Ø Mass spe:cLIulll (EI, M.+) m/z 278.

Claims

(1) A compound of formula I:

wherein R is alkyl of 1 to 6 carbon atoms; a substituted or unsubstituted aromatic N, O
or S heterocycle having 4 to 6 carbon and one hetero ring members; substituted or unsubstituted aryl of 6 to 10 carbon atoms, arylalkyl of 7 to 12 carbon atoms, benzhydryl or indanyl, in which the substituents are one to three members independently selected from the group consisting of alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, halo, perfluoroalkyl of 1 to 6 carbon atoms, perfluoroalkoxy of 1 to 6 carbon atoms or hydroxy; and R1 is aryl of 6 to 10 carbon atoms, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms or substituted aryl of 6 to 10 carbon atoms where the substituents are one to three members independently selected from the group consisting of alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon ations, alkylthio of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, halo, perfluoroalkyl of 1 to 6 carbon atoms, perfluoroalkoxy of 1 to 6 carbon atoms or hydroxy, for use in the treatment of mammals.

(2) A compound according to claim 1 wherein the treatment is for increasing the HDL cholesterol concentration in the blood of a mammal in need of increased HDL
cholesterol blood concentration.

(3) A compound of Claim 1 or 2 in which said compound is of formula 1 in which R is substituted phenyl where the substituents are two members of the group consisting of alkyl of 1 to 6 carbon atoms, perfluoroalkoxy of 1 to 6 carbon atoms, halo, or ortho substituted trymethylene or tetramethylene and R1 is alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms.

(4) A compound of Claim 1 or 2 in which said compound is of formula I in which R is substituted phenyl where the substituents are a halo and an alkyl group of 1 to 3 carbon atoms or ortho substituted trimethylene and R1 is alkyl of 1 to 3 carbon atoms, alkenyl of 2 to 4 carbon atoms or alkynyl of 2 to 4 carbon atoms.

(5) A compound of Claim 1 or 2 in which said compound is of formula I in which R is substituted phenyl where the substituents are chloro or fluoro in the 4- or5-position and an alkyl group of 1 to 3 carbon atoms and R1 is alkyl of 1 to 3 carbon atoms, alkenyl of 2 to 4 carbon atoms or alkynyl of 2 to 4 carbon atoms.

(6) A compound of Claim 1 or 2 in which said compound is selected from the group consisting of:
3-(5-Chloro-2-methylphenyl)-1-methyl-2-thioxo-imidazolidin-4-one;
3-(3-Chloro-2-methylphenyl)-1-methyl-2-thioxo-imidazolidin-4-one;
3-(4-Chloro-2-methylphenyl)-1-methyl-2-thioxo-imidazolidin-4-one;
3-(Indan-5-yl)-1-methyl-2-thioxo-imidazolidin-4-one;
3-(2,6-Diisopropylphenyl)-1-methyl-2-thioxo-imidazolidin-4-one;
3-(2-Ethyl-6-isopropylphenyl)-1-methyl-2-thioxo-imidazolidin-4-one;
3-(2-Ethyl-6-methylphenyl)-1-methyl-2-thioxo-imidazolidin-4-one;
3-(5-Chloro-2-methylphenyl)-1-ethyl-2-thioxo-imidazolidin-4-one;
3-(2,6-Dichlorophenyl)-1-ethyl-2-thioxo-imidazolidin-4-one;
1-Ethyl-3-(4-fluorophenyl)-2-thioxo-imidazolidin-4-one;
1-Ethyl-2-thioxo-3-(4-trifluoromethoxyphenyl)-imidazolidin-4-one;
3-(2,6-Dimethylphenyl)-1-ethyl-2-thioxo-imidazolidin-4-one;
1-Ethyl-3-isobutyl-2-thioxo-imidazolidin-4-one;
3-(2-Chlorophenyl)-1-ethyl-2-thioxo-imidazolidin-4-one;
1-Ethyl-3-(2-tolyl)-2-thioxo-imdazolidin-4-one;
3-(2-Chloro-6-methylphenyl)-1-ethyl-2-thioxo-imidazolidin-4-one;
1-Ethyl-3-(5-fluoro-2-methylohenyl)-2-thioxo-emedazolidin-4-one;
3-(2,6-Diisopropylphenyl)-1-ethyl-2-thioxo-imidazolidin-4-one;

l-Ethyl-2-thioxo-3-(2-trifluromethylphenyl)-imidazolidin-4-one;
1-Ethyl-3-(2-chloro-6-methylphenyl)-2-thioxo-imedazolidin-4-one;
3-(2-Ethyl-4-methylphenyl)-1-ethyl-2-thioxo-imidazolidin-4-one;
3-(2,4-Dichlorophenyl)-1-ethyl-2-thioxo-imidazolidin-4-one;
3-(2,4-Dimethylphenyl)-1-ethyl-2-thioxo-imidazolidin-4-one;
3-(2,5-Dhimethylphenyle)-1-ethyl-2-thioxo-imidazolidin-4-one;
l-Ethyl-2-thioxo-3-(2,4,5-trimethylphenyl)-imidazolidin-4-one;
1-Ethyl-3-(2-isopropylphenyl)-2-thioxo-imidazolidin-4-one;
l-Ethyl-3-(2-ethylphenyl)-2-thioxo-imidazolidin-4-one;
3-(5-Chloro-2-methylphenyl)-1-phenyl-2-thioxo-imidazolidin-4-one;
3-(5-Chloro-2-methylphenyl)-1-isopropyl-2-thioxo-imidazolidin-4-one;
3-(2,6-Dimethylphenyl)-1-isopropyl-2-thioxo-imidazolidin-4-one;
3-(2-Ethyl-6-methylphenyl)-1-isopropyl-2-thioxo-imidazolin-4-one;
1-Butyl-3-(4-fluorophenyl)-2-thioxo-imidazolidin-4-one;
1-Allyl-3-(2,6-dimethylphenyl)-2-thioxo-imidazolidin-4-one;
3-(2,6-Dimethylphenyl)-1-(prop-2-ynyl)-2-thioxo-imidazolidin-4-one;
3-(3-Chloro-4-methylpheinyl)-1-methyl-2-thioxo-imidazolidin-4-one 3-(2-Ethylphenyl)-1-methyl-2-thioxo-imidazolidin-4-one 1-Methyl-3-(2-isopropylphenyl)-2-thioxo-imidazolidin-4-one 3-(4-t-Butylphenyl)-1-methyl-2-thioxo-imidazolidin-4-one 1-Allyl-3-(5-chloro-2-methylphenyl)-2-thioxo-imidazolidin-4-one 3-(5-Chloro-2-methylphenyl)-1-(prop-2-ynyl)-2-thioxo-imidazolidin-4-one; or 1-Ethyl-3-(2-ethyl-6-isopropylphenyl)-2-thioxo-imidazolidin-4-one.
3-(2-chloro-6-methylphenyl)-1-methyl-2-thioxo-imidazolidin-4-one.
3-(2,6-dimethylphenyl)-1-methyl-2-thioxo-imidazolidin-4-one (7) Use of a compound of formula I as defined in any of claims 1 to 6 for the manufacture of a medicament for increasing the HDL cholesterol concentration in the blood of a mammal in need of increased HDL cholesterol blood concentration (8) A pharmaceutical composition comprising a compound of the formula I as defined in any of claims 1 to 6 and a pharmaceutically acceptable carrier (9) A method for increasing the HDL cholesterol concentration in the blood of a mammal in need of increased HDL cholesterol blood concentration, which comprisesadministering to said mammal, orally or parenterally, a compound of formula I asdefined in any of claims 1 to 6.

(10) A compound of formula I:

wherein R1 is alkyl of 1 to 6 carbon atoms and R is alkyl of 1 to 6 carbon atoms, naphthyl, benzhydryl, fluorophenylmethyl, phenethyl, 1-(fluorophenyl)ethyl, 5-chloro-2-methoxyphenyl, trifluoromethoxyphenyl, trifluoromethylphenyl, methylsulfanylphenyl, pyridyl or the group of formula II

where R2, R3 and R4 together are 2-chloro, 4-fluoro, 2,4-chloro or 2,6- chloro, or R2 is hydrogen, R3 is a halogen in 3-position and R4 is alkyl of 1 to 6 carbon atoms in 4-position, or R2 is alkyl of 1 to 6 carbon atoms and R3 and R4 are, independently, hydrogen or alkyl of 1 to 6 carbon atoms or R3 is a halogen and R4 is hydrogen;
or R1 is alkenyl of 2 to 6 carbon atoms, R is is the group of formula II
where R2 is alkyl of 1 to 6 carbon atoms and R3 and R4 are, independently, hydrogen or alkyl of 1 to 6 carbon atoms, or R2 is hydrogen and R3 and R4 taken together are ortho substituted trimethylene or tetramethylene, or R2 is alkyl of 1 to 6 carbon atoms, R3 is halogen and R4 is hydrogen, or R2 is hydrogen, R3 is halogen in 3-position and R4 is alkyl of 1 to 6 carbon atoms in 4-position;
or when R1 is alkynyl of 2 to 6 carbon atoms, R is a group of formula II
where any two of R2, R3 and R4 are, independently, alkyl of 1 to 6 carbon atoms,halo, perfluoralkyl of 1 to 6 carbon atoms, perfluoroalkoxy of 1 to 6 carbon atoms, or, taken together, are ortho substituted trimethylene or tetramethylene;
or when R1 is aryl of 6 to 10 carbon atoms or arylalkyl of 7 to 12 carbon atoms, R is the group of formula II
where R2 is alkyl of 1 to 6 carbon atoms, R3 is a halogen and R4 is hydrogen, or R2 is hydrogen, R3 is a halogen in 3-position and R4 is alkyl of 1 to 6 carbon atoms in 4-position.

(11) A compound according to Claim 10 of formula:

in which R1 is alkyl of 1 to 6 carbon atoms or alkenyl of 2 to 6 carbon atoms;
R2 is alkyl of 1 to 6 carbon atoms and R3 and R4 are, independently, hydrogen or alkyl of 1 to 6 carbon atoms; or R2 is hydrogen and R3 and R4 taken together are ortho substituted trimethylene or tetramethylene.

(12) A compound according to Claim 11 in which R3 and R4 are hydrogen, R1 is methyl or ethyl and R2 is alkyl of 1 to 3 carbon atoms.

(13) The compound according to Claim 11 or 12 which is 3-(2-ethylphenyl)-1-methyl-2-thioxo-imidazolidin-4-one.

1-methyl-3-(2-isoptopylphenyl)-2-thioxo-imadazolin-4-one.
1-ethyl-3-(2-tolyl)-2-thioxo-imidazolin-4-one.
1-ethyl-3-(2-isopropylphenyl)-2-thioxo-imidazolin-4-one.
1-ethyl-3-(2-ehylphenyl)-2-thioxo-imdazolin-4-one.

(14) A compound according to Claim 11 in which R4 is hydrogen, R1 is methyl, ethyl or allyl, R2 is alkyl of 1 to 3 carbon atoms and R3 is alkyl of 1 to 3 carbon atoms or R2 is hydrogen and R3 and R4 are ortho substituted trimithylene or tetramethylene.

(15) The compound according to Claim 14 which is 3-(2-ethyl-6-methylphenyl)-1-methyl-2-thioxo-imidazolidin-4-one.
3-(2,6-dimethylphenyl)-1-ethyl-2-thioxo-imidazolidin-4-one.
3-(2,6-dimethylphenyl)-1-isopropyl-2-thioxo-imifsxolidin-4-one .
1-allyl-3-(2,6-dimethylphenyl)-2-thioxo-imidazolidin-4-one.
3-(2-ethyl-6-isopropylphenyl)-1-methyl-2-thioxo-imidazolidin-4-one.
1-ethyl-3-(2-ethyl-6-isopropylphenyl)-2-thioxo-imidazolidin-4-one.

(16) A compound according to Claim 11 in which R1 is methyl, ethyl or allyl and R2, R3 and R4 are, independently, alkyl of 1 to 3 carbon atoms.

(17) A compound according to Claim 16 which is 1-ethyl-2-thioxo-3-(2,4,5-trimethyphenyl)-imidazolidin-4-one.

(18) A compound according to Claim 10 of formula:

in which R1 is alkyl of 1 to 6 carbon atoms;

R2 and R3 represent 2,4-dichloro or 2,6-dichloro;
or R2 is 2-chloro or 4-fluoro and R3 is hydrogen.

(19) The compound according to Claim 18 which is 3-(2,6-dichlorophenyl)-1-ethyl-2-thioxo-imidazolidin-4-one;
1-ethyl-3-(4-fluorophenyl)-2-thioxo-imidazolidin-4-one;
3-(2-chlorophenyl)-1-ethyl-2-thioxo-imidazolidin-4-one;
3-(2,4-dichlorophenyl)-1-ethyl-2-thioxo-imdazolidin-4-one;
3-(4-fluorophenyl)-1-isopropyl-2-thioxo-imidazolidin-4-one;
1-butyl-3-(4-fluorophenyl)-2-thioxo-imidazolidin-4-one.
(20) A compound according to Claim 10 of formula:

in which R1 is alkynyl of 2 to 6 carbon atoms; and R2 and R3 are, independently, alkyl of 1 to 6 carbon atoms, halo, perfluoralkyl of 1 to 6 carbon atoms, perfluoralkoxy of 1 to 6 carbon atoms, or, taken together, R2 and R3 are ortho substituted trimethylene or tetramethylene.

(21) A compound of according to Claim 20 in which R1 is ethynyl, propargyl or butynyl.

(22) The compound according to Claim 20 or 21 which is 3-(2,6-dimethylphenyl)-1-(prop-2-ynyl)-2-thioxo-imidazolidin-4-one;
3-(5-chloro-2-methylphenyl)-1-(prop-2-ynyl)-2-thioxo-imidazolidin-4-one;
3-(4-chloro-2-methylphenyl)-1 -(prop-2-ynyl)-2-thioxo-imidazolidin-4-one;

(23) A compound according to Claim 10 of formula:

in which R1 is alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, aryl of 6 to10 carbon atoms or arylalkyl of 7 to 12 carbon atoms;
R2 is alkyl of 1 to 6 carbon atoms, R3 is a halogen and R4 is hydrogen; or R2 is hydrogen, R3 is a halogen in 3-position and R4 is alkyl of 1 to 6 carbon atoms in 4-position.

(24) A compound according to Claim 23 in which R1 is alkyl of 1 to 3 carbon atoms, allyl or phenyl, R2 is alkyl of 1 to 3 carbon atoms, R3 is chloro or fluoro and R4 is hydrogen.

(25) The compound according to Claim 23 or 24 which is 3-(5-chloro-2-methylphenyl)-1-methyl-2-thioxo-imidazolidin-4-one.
3-(3-chloro-2-methylphenyl)-1-methyl-2-thioxo-imidazolidin-4-one.
3-(4-chloro-2-methylphenyl)-1-methyl-2-thioxo-imidazolidin-4-one.
3-(5-chloro-2-methylphenyl)-1-ethyl-2-thioxo-imidazolidin-4-one.
3-(2-chloro-6-methylphenyl)-1-ethyl-2-thioxo-imidazolidin-4-one.
1-ethyl-3-(5-fluoro-2-methylphenyl)-2-thioxo-imidazolidin-4-one.
3-(5-chloro-2-methylphenyl)-1-phenyl-2-thioxo-imidaxolidin-4-one.
3-(5-chloro-2-methylphenyl)-1-isopropyl-2-thioxo-imidazolidin-4-one.
1-Allyl-3-(5-chloro-2-methylphenyl)-2-thioxo-imidazolidin-4-one (26) A compound according to Claim 10 of formula I in which R1 is alkyl of 1 to 6 carbon atoms; and R is alkyl of 1 to 6 carbon atoms, naphthyl, benzhydryl, fluorophenylmethyl, phenethyl, 1-(fluorophenyl)ethyl, 5-chloro-2-methoxyphenyl, trifluoromethoxyphenyl, trifluoromethylphenyl, methylsulfanylphenyl or pyridyl.

(27) A compound according to Claim 26 in which R1 is alkyl of 1 to 6 carbon atoms;
and R is alkyl of 1 to 6 carbon atoms, 2-naphthyl, benzhydryl, 4-fluophenymethyl, phenethyl, 1-(4-fluorophenyl)ethyl, 5-chloro-2-methoxyphenyl, 4-trifluoro-methoxyphenyl, 2-trifluoromethylphenyl, 2-methylsulfanylphenyl or 3-pyridyl.

(28) The compound according to Claim 26 or 27 which is 3-benzhydryl-1-methyl-2-thioxo-imidazolidin-4-one;
1-methyl-3-(pyridin-3-yl)-2-thioxo-imidazolidin-4-one;
3-(5-chloro-2-methoxyphenyl)-1-methyl-2-thioxo-imidazolidin-4-one;
3-(5-chloro-2-methoxyphenyl)-1-ethyl-2-thioxo-imidazolidin-4-one;
1-ethyl-2-dlioxo-3-(4-trifluoromethoxyphenyl)-imidazolidin-4-one;
1-ethyl-3-(4-fluorobenzyl)-2-thioxo-imidazolidin-4-one;
1-ethyl-3-isobutyl-2-thioxo-imedazolidin-4-one;
1-ethyl-3-(naphthalen-2-yl)-2-thioxo-imidazolin-4-one;
1-ethyl-2-thioxo-3-(2-trifluromethylphenyl)-imidazolidin-4-one;
1-ethyl-3-[1-(4-flurophenyl)-ethyl]-2-thioxo-imidazolidin-4-one;
1-ethyl-3-phenethyl-2-thioxo-imidazolidin-4-one;

1-ethyl-3-(2-methylsulfanylphenyl)-2-thioxo-imidazolidin-4-one.

(29) Process for the preparation of a compound as defined in any of claims 1 to 28 comprising reacting the corresponding compound of formula A

in which R2 is as defined in any of claims 1 to 28 and X is halogen, with R1-NH2 in which R1 is as defined in any of claims 1 to 28, to give a compound of formula 2(a) in which R1 and R2 are as previously defined herein and reacting the compound offormula 2(a) with R-NCS in the presence of a base to provide either the compound of formula (3a) or of formula (4) and thereafter cyclising the compound of formula (3a) to the compound of formula (4) by refluxing in the presence of a base.